Autoantibodies to Tumor-Associated Antigens in Breast Carcinoma

Ettie Piura; Benjamin Piura

doi:10.1155/2010/264926

Autoantibodies to Tumor-Associated Antigens in Breast Carcinoma

Piura, Ettie;Piura, Benjamin 2010-11-21 00:00:00 Hindawi Publishing Corporation Journal of Oncology Volume 2010, Article ID 264926, 14 pages doi:10.1155/2010/264926 Review Article Autoantibodies to Tumor-Associated Antigens in Breast Carcinoma 1 2 Ettie Piura and Benjamin Piura Department of Obstetrics and Gynecology, Sapir Medical Center, Sackler School of Medicine, University of Tel-Aviv, Kfar-Saba 44281, Israel Unit of Gynecologic Oncology, Department of Obstetrics and Gynecology, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel Correspondence should be addressed to Benjamin Piura, piura@bgu.ac.il Received 21 July 2010; Revised 4 September 2010; Accepted 19 October 2010 Academic Editor: Aysegula A. Sahin Copyright © 2010 E. Piura and B. Piura. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identiﬁed in the circulation of patients with cancer. This paper will focus on recent knowledge related to circulating AAbs to TAAs in breast carcinoma. So far, the following TAAs have been identiﬁed to elicit circulating AAbs in breast carcinoma: p53, MUC-1, heat shock proteins (HSP-27, HSP-60, and HSP-90), HER2/neu/c-erb B2, GIPC-1, c-myc, c-myb, cancer-testis antigens (NY-ESO-1), BRCA1, BRCA2, endostatin, lipophilin B, cyclin B1, cyclin D1, ﬁbulin, insulin-like growth factor binding protein 2 (IGFBP-2), topoisomerase II alpha (TOPO2α), and cathepsin D. Measurement of serum AAbs to one speciﬁc TAA only is of little value for screening and early diagnosis of breast carcinoma; however, assessment of AAbs to a panel of TAAs may have promising diagnostic potential. 1. Introduction over 2,000 candidate TAAs in many types of human cancer have been identiﬁed and separated into six categories [5, 8– The development of circulating autoantibodies (AAbs) to 11]: (1) diﬀerentiation antigens (expressed by cancers and tumor-associated antigens (TAAs) has been observed to a restricted subset of normal cells, e.g., tyrosinase, melan- be associated with cancer [1, 2]. Unlike traditional tumor A/MART-1, NY-BR-1, and gp100), (2) mutational antigens markers (e.g., CA-15-3, CA-19-9, CA-125, and CEA), which (e.g., CDK4, β-catenin, caspase-8, and p53), (3) ampliﬁ- are soluble proteins shed by bulky tumors, serum AAbs to cation (overexpression) antigens (e.g., c-erb B2/HER2/neu, TAAs are detectable even when the tumor is very small [2]. NY-C0-58, and p53), (4) splice variant antigens (e.g., NY- Thus, the identiﬁcation of AAbs to TAAs could potentially CO-37/PDZ-45, and ING1), (5) viral antigens (e.g., HPV be used as a novel tool for screening and early diagnosis and EBV), and cancer-testis (CT) antigens (e.g., NY-ESO- of cancer [2–6]. Sahin et al. [7] introduced in 1995 a 1, MAGE-A, and LAGE-1). The humoral immune response method called SEREX (serological analysis of recombinant elicited by TAAs could have two major clinical applications cDNA expression libraries) that has broad applicability to [9]: (1) AAbs to TAAs could represent novel biomarkers the analysis of the humoral immune response to cancer. for cancer diagnosis, prognosis, monitoring, and prediction Originally, they had used mRNA isolated from tumor tissue of response to chemotherapy, (2) TAAs might be used with the assumption that speciﬁc TAAs could be isolated. as targets for immunotherapy of cancer. Notwithstanding, This has turned out to be incorrect, since there is no such eﬀorts to predict cancer based on autoimmunity to either thing as a TAA that is only expressed in tumors. Thus, the an individual TAA or even tailor-made panel of TAAs have SEREX method as described by the original authors has been not yet resulted in serologic biomarkers with deﬁnitive highly modiﬁed and uses nowadays cDNA libraries from a predicting speciﬁcity and sensitivity [12]. It has, however, variety of cell lines and not just from tumor tissues. So far, been shown by some investigators that the use of tailor-made 2 Journal of Oncology panel of TAAs, rather than individual TAAs, enhances the circulating AAbs to speciﬁc breast carcinoma TAAs have been likelihood of detecting cancer-associated AAbs with potential identiﬁed and investigated. In breast carcinoma, like in other diagnostic value [3, 12]. malignancies, the use of tailor-made panel of TAAs, rather In the USA, breast carcinoma is diagnosed in approxi- than individual TAAs, enhances the likelihood of detecting mately 193,000 women and 2,000 men yearly with an age- cancer-associated AAbs with potential diagnostic value. adjusted incidence of 125 new cases/100,000 women/year This paper will review the up-to-date knowledge related and 1 new case/100,000 men/year, and it causes approxi- to AAbs against individual TAAs in breast carcinoma. Table 1 mately 41,000 deaths (40,500 women and 500 men) each shows the frequency of identiﬁed AAbs to breast carcinoma year [13, 14]. Breast carcinoma is the ﬁrst most common TAAs. cancer among women (27% of all cancers in women) and the second most common cause of death from cancer, after lung carcinoma, in women (15% of all cancer deaths in women) 2. Autoantibodies to p53 Protein [13]. The National Cancer Institute (NCI) has estimated that 12.7% (1/8) of women born today in the USA will be The wild-type p53 gene is a tumor suppressor gene located diagnosed with breast carcinoma at some time in their lives on chromosome 17p13 and encodes a 53-kDa nuclear phos- [15]. Theﬁve-yearsurvivalrateoverall of womenwithbreast phoprotein that normally acts as a guardian of the integrity carcinoma in the USA is about 90% [14]. of the genome [27, 44, 45]. Mutations in p53 are the most Worldwide, breast carcinoma is by far the most frequent common genetic changes found in human malignancies cancer among women with an estimated 1.38 million new and the mutational status of p53 is prognostic in many cases diagnosed in 2008 (23% of all malignancies in women) malignancies [46]. In breast carcinoma, p53 mutations have and ranks second overall (10.9%), after lung carcinoma, of been shown to be associated with worse overall and disease- all malignancies in both sexes [16]. The estimated incidence free survival, independent of other risk factors, and have of breast carcinoma in 2008 worldwide has been 39 new been implicated in resistance to anticancer therapies [47, cases/100,000 women. The incidence has been estimated to 48]. Missense point mutations, which represent more than vary from 19.3 in Eastern Africa to 89.9 in Western Europe, 85% of gene abnormalities, lead to a conformational change and is high (greater than 80) in developed countries (except which stabilizes the p53 protein and allows it to accumulate Japan) and low (less than 40) in most of the developing in the nucleus to relatively high levels [27, 44, 45, 49–51]. countries [16]. Breast carcinoma has been estimated to cause Accumulation of the mutant p53 in tumor cells can elicit 458,000 deaths in 2008 worldwide (13.7% of all cancer a humoral immune response leading to the production of deaths in women and 6% of all cancer deaths in both anti-p53 AAbs [27]. Initially, it was thought that only tumors sexes). The estimated mortality from breast carcinoma in with missense p53 mutations resulting in p53 overexpression 2008 worldwide has been 12.5 deaths/100,000 women. Breast can elicit anti-p53 AAbs [27, 52–54]. Later on, however, carcinoma is the most frequent cause of death from cancer in anti-p53 AAbs have also been detected in sera from patients women worldwide and the ﬁfth cause of death from cancer, with tumors lacking p53 overexpression. Induction of anti- after lung, stomach, liver, and colorectal carcinoma, in both p53 AAbs in these patients might be due to the unusual sexes [16]. presentation of large amounts of wild-type p53 from necrotic Current screening modalities for breast carcinoma diag- large tumors or metastases [27, 55]. Recently, it has been nosis include mammography, ultrasound (US), and mag- shown that anti-p53 AAbs are directed against immunodom- netic resonance imaging (MRI); however, there is still an inant epitopes localized in the amino and carboxy terminal urgent need to develop an alternative modality of screening ends of the p53-protein, unrelated to the mutational hot for earlier diagnosis [17]. The use of serum-soluble tumor spot [27, 51, 56–58]. Epithelial ovarian carcinomas have antigens, such as CA-15-3 glycoprotein, as biomarkers for been regarded as a tumor entity associated with the highest detection of breast carcinoma has been limited by their frequency (13%–46%) of circulating anti-p53 AAbs [59]; insuﬃcient speciﬁcity and sensitivity, particularly for organ nevertheless, breast carcinomas are also associated with a conﬁned early-stage disease. Consequently, CA-15-3 is not considerable incidence (2.8%–47.5%) of serum anti-p53 recommended for use in the screening or detection of breast AAbs. Thus, breast carcinomas, alongside epithelial ovarian carcinoma [18–21]. This is in part due to the elevation of CA- carcinomas, are among the most immunogenic malignancies 15-3 in benign conditions including breast, liver, and kidney inducing anti-p53 AAbs response. Indeed, while mutation disorders and other cancers [22]. Thus, there is a need to of p53 appears a seminal event in carcinogenesis and is discover novel biomarkers, such as AAbs to speciﬁc breast present in ∼30% of breast carcinoma patients, it is still carcinoma TAAs, for screening, early diagnosis, prediction unclear why only a subset of p53 mutation-positive breast of prognosis, and monitoring of treatment. There is also carcinoma patients (∼50%) generates anti-p53 AAbs [27]. It a need to develop new therapeutic approaches, such as has been suggested that only p53 mutations that are localized immunotherapy, for the management of breast carcinoma. in exons 5 and 6 with an altered protein conformation and TheestablishmentofAAbstoTAAsasbiomarkersfor breast that bind to HSP-70 are associated with anti-p53 AAbs [54, carcinoma and the development of successful immunother- 58]. Further studies, however, have demonstrated that other apeutic strategies require the identiﬁcation and characteri- factors contribute to the humoral immune response to p53 zation of immunogenic breast carcinoma TAAs that will be protein and suggested that the capacity to elicit a humoral recognized by the host immune system. Thus far, only few immune response is linked to the biological background Journal of Oncology 3 Table 1: Frequency of identiﬁed circulating AAbs to TAAs in breast carcinoma. AAbtoTAA Positive Total % Comment Reference Promising diagnostic potential when 22 94 23.4 p53 [23] incorporated in AAb assays to a panel of a a 6 40 15.0 TAAs p53 [24] 11 24 45.8 Association with higher risk for relapse. Correlation to higher stage, lymph node p53 [25] 31 144 21.5 metastasis, negative ER, positive c-erbB-2 and worse survival. Correlated neither with p53 cytosolic p53 8 101 7.9 [26] assay nor with prognostic factors. Promising diagnostic potential when p53 22 220 10 incorporated in AAb assays to a panel of [1] TAAs Summary of 15 studies (1979–1999). Frequency of AAbs: 2.8%–47.5%. Few p53 [27] 296 2006 14.7 studies showed association with high grade and poor survival. Promising diagnostic potential when 19 94 20.2 MUC1 incorporated in AAb assays to a panel of [23] a a 9 40 22.5 TAAs. No correlation to circulating mucin levels MUC1 [28] 224 8.3 or stage of disease. Inverse correlation to extent of disease. b b b 36 140 25.7 MUC1 [29] Suggested role in protection against c c c 11 61 18.0 disease progression. Promising diagnostic potential when MUC1 20 100 20 incorporated in AAb assays to a panel of [1] TAAs. HSP-27 [30] 219 579 37.8 Association with improved survival. 18 58 31 HSP-60 Promising diagnostic potential. [31] a a a 16 49 33 Correlation to extent of disease. HSP-90 46 125 36.8 [32] Promising diagnostic potential. HSP-90 135 214 63.1 Association with higher mortality rate. [33] Promising diagnostic potential when 16 94 17.0 HER2/neu incorporated in autoantibody assays [23] a a 5 40 12.5 against a panel of TAAs. HER2/neu oncoprotein elicits an HER2/neu [34] 11 20 55 immune response and may be used as a target for speciﬁc immunotherapy. 12 107 11.2 Correlation to positive HER2/neu status b d d d HER2/neu 9 44 20.4 [35] in the primary tumor (P = .03). e e 3 63 4.8 Incidence is lower in advanced-stage disease compared to early-stage disease. HER2/neu [36] 345 6.6 Suggested role in limiting disease progression. Promising diagnostic potential when HER2/neu 30 225 13 incorporated in AAb assays to a panel of [1] TAAs. GIPC-1 [37] 17 22 77 Promising diagnostic potential. Promising diagnostic potential when 12 94 12.7 c-myc [23] incorporated in autoantibody assays a a 3 40 7.5 against a panel of TAAs No correlation to c-myb status in the c-myb [38] 31 72 43 primary tumor. 4 Journal of Oncology Table 1: Continued. AAbtoTAA Positive Total % Comment Reference Promising diagnostic potential when 25 94 26.6 NY-ESO-1/ LAGE-1 [23] incorporated in autoantibody assays a a 3 40 7.5 against a panel of TAAs No diagnostic potential, even if 8 94 8.5 BRCA1 [23] incorporated in autoantibody assays a a a 1 40 2.5 against a panel of TAAs Promising diagnostic potential when 32 94 34.0 BRCA2 incorporated in autoantibody assays [23] a a 9 40 22.5 against a panel of TAAs Inverse correlation to extent of disease. b b b 24 36 66.6 No correlation to circulating levels of Endostatin [39] c c c 25 59 42.4 endostatin. Association with better prognosis in advanced-stage disease. 20 74 27.0 Correlation to extent of disease. Lipophilin B [40] c c c 13 35 37.1 Promising diagnostic potential. Cyclin D1 3 40 7.5 Questionable diagnostic potential [1] Correlation to higher level of tumor Cyclin B1 3 7 42.8 cyclin B1 expression. Questionable [41] diagnostic potential. Fibulin [42] 15 20 75 Promising diagnostic potential. IGFBP2 [1] 21 142 15 Questionable diagnostic potential IGFBP2 [43] 4 80 5 Questionable diagnostic potential TOPO2α [1] 8 115 7 Questionable diagnostic potential Cathepsin D [1] 5 100 5 Questionable diagnostic potential Ductal carcinoma in situ (DCIS). Early-stage disease. Advanced-stage disease. HER2/neu-positive tumor. HER-2/neu-negative tumor. −4 of the patients [27, 52]. It is possible that for an identical controls (P< 10 )[27]. Since serum anti-p53 AAbs mutation, the humoral immune response is dependent on are truly rare in the normal population, the speciﬁcity of the speciﬁc combination of MHC class I and II molecules this assay for the detection of breast carcinoma has been expressed by each individual [27]. estimated to attain 95%. Nevertheless, since anti-p53 AAbs were present on the average in the sera of only 15% of Dalifard et al. [26] demonstrated by ELISA in 1999 that breast carcinoma patients, the sensitivity of this assay for the anti-p53 AAbs were present in the sera of 8/101 (7.9%) detection of breast carcinoma has been estimated to reach patients with breast carcinoma. The presence of serum anti- only 30% [27]. Five studies [58, 60, 63, 65, 67] indicated p53 AAbs correlated neither with p53 cytosolic assay nor with that serum anti-p53 AAbs are found in patients with tumors prognostic factors. The authors concluded that serum anti- that have high grades and/or that are negative for steroid p53 AAb assay is not useful for the selection of patient groups with poor prognosis [26]. hormone receptors, two clinical parameters known to be associated with p53 mutations and bad prognosis. Two Soussi [27] surveyed the literature from 1979 through studies [67, 68] found an association between serum anti- 1999 on anti-p53 AAbs in the sera of patients with various p53 AAbs and short survival whereas one study [71] did types of cancer. Serum anti-p53 AAbs were present in not ﬁnd any association, and another study [66]found an 1600/9489 (16.8%) patients with diﬀerent malignancies and −4 association with good survival. in 35/2404 (1.4%) healthy controls (P< 10 ). Fifteen studies [52, 54, 58, 60–71] examined anti-p53 AAbs in the Regele et al. [24] demonstrated by ELISA in 2003 that sera of breast carcinoma patients. The frequency of anti- serum anti-p53 AAbs were present in 11/24 (45.8%) patients p53 AAbs in the sera of breast carcinoma patients ranged at initial diagnosis of breast carcinoma. In seven of these 11 patients, therapy was paralleled by decreasing anti-p53 AAb in these studies from 2.8% to 47.5%. Overall, the presence of anti-p53 AAbs was demonstrated in the sera of 296/2006 titers; in four, relapse was preceded by an increase of the titer. (14.7%) breast carcinoma patients [27]. χ test showed that Two patients, who initially tested negative, seroconverted the frequency of anti-p53 AAbs was signiﬁcantly higher in to anti-p53 AAb positivity upon relapse. The authors [24] the sera of breast carcinoma patients compared to healthy concluded that monitoring of serum anti-p53 AAbs during Journal of Oncology 5 followup can be informative about the clinical course of the 1/10 (10%) colon carcinoma patients. Overall, the presence disease and the development of breast carcinoma relapse can or absence of serum anti-MUC1 AAbs did not correlate be preceded by an increase of serum anti-p53 AAb titer. with the levels of circulating mucin or stage of disease [28]. Gao et al. [25] showed by ELISA in 2005 that serum von Mensdorﬀ-Pouilly et al. [29] demonstrated by sandwich anti-p53 AAbs were present in 31/144 (21.5%) patients with enzyme-linked immunoassay in 1996 that anti-MUC1 AAbs breast carcinoma and 12/242 (4.9%) healthy controls. The were present in the sera of 2/96 (2.1%) healthy controls, presence of serum anti-p53 AAbs was associated with several 15/40 (37.5%) patients with benign breast tumor, 36/140 poor prognostic factors including higher clinical stage (P = (25.7%) patients with early-stage breast carcinoma and .0233), lymph nodes metastasis (P = .0033), negative ER 11/61 (18%) patients with advanced-stage breast carcinoma. expression (P = .0250) and positive HER2/c-erbB-2 status Serum anti-MUC1 AAbs were elevated in 24/74 (32.4%) (P = .0227). There was also a strong correlation between node-negative patients and in 12/59 (20.3%) node-positive serum anti-p53 AAbs and tumor immunohistochemical patients andabsolutevalueswerehigherinnode-negative positivity for p53 (P< .0001). The authors [25] speculated patients (P = .0168). There was an inverse correlation that serum anti-p53 AAbs could serve as a useful and between positivity for serum anti-MUC1 AAbs and extent convenient marker for the detection and prognosis of breast of disease; while 3/6 (50%) patients with a carcinoma in carcinoma. situ were positive, only 1/15 (6.7%) patients with more Chapman et al. [23] showed by ELISA in 2007 that than ﬁve nodes involved had elevated levels of anti-MUC1 preoperative serum anti-p53 AAbs were present in 22/94 AAbs. All seven patients with distant metastases at ﬁrst (23.4%) patients with newly diagnosed breast carcinoma diagnosis were anti-MUC1 AAb-negative. Twenty-eight of and 6/40 (15%) patients with ductal carcinoma in situ. 133 patients had a recurrence during followup; 23 (82%) of Positive seroreactivity was deﬁned as an absorbance value these 28 patients were anti-MUC1 AAb-negative at the time greater than the mean plus two standard deviations of a of ﬁrst diagnosis. The 5-year survival of 13 patients who had normal cohort. The sensitivity and speciﬁcity were 24% and elevated pretreatment serum levels of CA-15-3 (>30 U/mL) 96%, respectively, for breast carcinoma, and 15% and 96%, and were anti-MUC1 AAb-positive was better than the 5- respectively, for ductal carcinoma in situ. The authors [23] year survival of 41 patients who had elevated pretreatment concluded that measurement of serum AAbs to p53 protein serum levels of CA-15-3 and were anti-MUC1 AAb-negative only is of little value for screening and early diagnosis of (100% versus 71%, P = .0457). The authors [29]suggested breast carcinoma; however, AAbs to p53 may have promising that a natural humoral immune response to MUC1 seems diagnostic potential when incorporated in AAb assays against to protect against disease progression, while lack of immune apanel of TAAs. reaction, or immune tolerance developing in the course of Lu et al. [1] demonstrated with ELISA in 2008 that AAbs disease, could be an additional risk factor more frequently to p53 protein were present in the sera of 22/220 (10%) associated with an unfavorable outcome. breast carcinoma patients compared to 2/200 (1%) healthy Chapman et al. [23] showed by ELISA in 2007 that serum controls. It has been concluded that AAbs to p53 have no anti-MUC1 AAbs were present in 19/94 (20.2%) patients diagnostic potential when examined alone; however, they with newly diagnosed breast carcinoma and 10/40 (25%) may possibly have diagnostic potential when incorporated in patients with ductal carcinoma in situ. Positive seroreactivity AAB assays to a panel of TAAs. wasdeﬁnedasanabsorbancevalue greaterthanthe mean plus two standard deviations of a normal cohort. The sensitivity and speciﬁcity were 20% and 98%, respectively, for breast carcinoma, and 23% and 98%, respectively, for 3. Autoantibodies to MUC1 Protein ductal carcinoma in situ. The authors [23] concluded that Polymorphic epithelial mucin (PEM, MUC1), a human measurement of serum AAbs to MUC1 protein only is mucin family member, is a high-molecular-weight (over of little value for screening and early diagnosis of breast 400 kDa) transmembrane glycoprotein. It is expressed in a carcinoma; however, AAbs to MUC1 may have promising hyperglycosylated form and low levels by many types of diagnostic potential when incorporated in AAb assays against normal epithelial cells and in a hypoglycosylated form and apanel of TAAs. Lu at al. [1] observed an increased AAb response to p53, high levels by most epithelial adenocarcinomas including breast and ovarian carcinoma [72, 73]. About one-quarter of HER-2, MUC1, topoisomerase II alpha (TOPO2α), insulin- breast and ovarian carcinoma patients have circulating AAbs like growth factor binding protein 2 (IGFBP2), cyclin D1, and Cathepsin D in breast carcinoma patients. Nonetheless, to MUC1, either free or bound to immune complexes. While the presence of these immune complexes has prognostic the most frequently encountered AAb response was directed signiﬁcance in cancer patients, the signiﬁcance of free AAbs against MUC1 protein, which was detected in 20/100 (20%) to MUC1 is less clear [74]. AAbs to MUC1 have been breast carcinoma patients compared to 3/100 (3%) healthy described and correlated with a more favorable prognosis; controls [1]. Obviously, serum AAb-assay against MUC1 protein only thus, it seems that risk for breast carcinoma might be reduced by preexisting MUC1-speciﬁc immunity [75, 76]. is of little value for screening and early diagnosis of breast Using ELISA, Kotera et al. [28] demonstrated in 1994 that carcinoma; however, AAbs to MUC1 may have promising diagnostic potential when incorporated in AAb assays against anti-MUC1 AAbs were present in the sera of 2/24 (8.3%) breast carcinoma, 2/12 (16.7%) pancreatic carcinoma, and a panel of TAAs. Moreover, there is support for the notion 6 Journal of Oncology that preexisting AAbs to MUC1 may reduce the risk of HER-2 status [31]. It seems that measuring AAbs to HSP- developing breast carcinoma and presence of AAbs to MUC1 60 has promising diagnostic potential for early detection in breast carcinoma is correlated with a more favorable of breast carcinoma; however, this is still inconclusive and prognosis. further studies are needed. Conroy et al. [32] demonstrated by ELISA in 1995 that serum AAbs to HSP-90 were present in 46/125 (36.8%) breast carcinoma patients. Seropositivity was deﬁned as a value 4. Autoantibodies to Heat-Shock Proteins greater than the mean value observed in normal controls plus three standard deviations. Multivariate analysis indicated Heat-shock proteins (HSPs) are cytoplasmic proteins that act as molecular chaperones for protein molecules in various that the presence of serum AAbs to HSP-90 (P< .04) intracellular processes. They play an important role in and the presence of axillary lymph node invovlement (P< protein-protein interactions, including folding and confor- .001) correlated with the development of metastases [32]. mation and prevention of inappropriate protein aggregation. Moreover, the presence of serum AAbs to HSP-90 correlated They are called heat-shock proteins since they were ﬁrst with the development of metastases even in patients without discovered in cells exposed to high temperatures. How- axillary lymphnodeinvolvement [32]. In 1998, Conroy et ever, their synthesis is also accentuated under other stress al. [33] showed by ELISA that serum AAbs to HSP-90 were present in 135/214 (63.1%) breast carcinoma patients before conditions, such as exposure of the cell to inﬂammation, infection, ischemia, toxins, cytotoxic drugs, and malignant surgery and 127/200 (63.5%) breast carcinoma patients transformation. HSPs have been classiﬁed into families after surgery. Mortality rate from breast carcinoma was greater in women testing positive for AAbs to HSP-90 than according to their molecular weight [77–79]. Overexpression of HSP-27 in breast carcinoma has been those testing negative for AAbs to HSP-90. Although the associated with shorter disease-free survival [30, 80, 81]. diﬀerence between the two groups did not attest statistical Conroy et al. [30] demonstrated by ELISA in 1998 that signiﬁcance, the authors have concluded that there appears to serum AAbs to HSP-27 were present in 219/579 (37.8%) be an association between higher mortality rate from breast carcinoma and presence of serum AAbs to HSP-90 [33]. breast carcinoma patients compared to 1/53 (1/9%) healthy subjects (P< .001). The mortality rate was lower in women with AAbs to HSP-27 than in those who lacked such AAbs (P = .006). Thus, a signiﬁcant association has been 5. Autoantibodies to found between the presence of serum AAbs to HSP-27 and HER2/Neu/c-ErbB2 (p185) Protein improved survival in breast carcinoma patients [30]. HSP-60 is an abundant, highly conserved protein mostly HER2/Neu/ErbB2 is a member of the epidermal growth localized in the mitochondrial matrix. It plays a role in factor receptor (EGFR) family that is ampliﬁed and overex- the regulation of various cellular functions and assists in pressed in 20%–30% of breast carcinomas. HER2-positive mitochondrial protein folding, unfolding, and degradation. breast carcinoma yields a poor patient prognosis due to HSP-60 is involved also in the process of apoptosis and a high incidence of metastases and intrinsic resistance to interacts with proteins implicated in cell cycle regulation endocrine and conventional chemotherapy. Treatments that [31]. With use of ELISA, Desmetz et al. [31] demonstrated target HER2 expression in cancer cells have been shown to the presence of serum AAbs to HSP-60 (seropositivity was be useful strategies to signiﬁcantly reverse the malignancy deﬁned as a value greater than the mean of the normal induced by HER2 overexpression [82]. population plus two standard deviations) in 16/49 (32.6%) Serum anti-HER2 AAbs were detected by ELISA in ductal carcinoma in situ (DCIS) patients and 18/58 (31%) 16/94 (17%) patients with newly diagnosed breast carcinoma early-stage breast carcinoma patients compared to 4/93 and 5/40 (12.5%) patients with ductal carcinoma in situ (4.3%) healthy subjects. This corresponded to a signiﬁcant [23]. Positive seroreactivity was deﬁned as an absorbance diﬀerence between DCIS patients (P< .0001) or early-stage value greater than the mean plus two standard deviations breast carcinoma patients (P< .0001) and healthy controls. of a normal cohort. The sensitivity and speciﬁcity were The frequency of AAbs to HSP-60 was signiﬁcantly higher 18% and 94%, respectively, for breast carcinoma, and 13% in high-grade DCIS patients (11/23, 47.8%) compared to and 94%, respectively, for ductal carcinoma in situ. It has low-grade DCIS patients (5/26, 19.2%) (P = .0188). This been concluded that measurement of serum AAbs to HER2 corresponded to a higher signiﬁcant diﬀerence between high- protein only is of little value for screening and early diagnosis grade DCIS patients and healthy controls (P< .0001) than of breast carcinoma;however,AAbstoHER2may have between low-grade DCIS patients and healthy controls (P = promising diagnostic potential when incorporated in AAb .0233) [31]. The diagnostic performance (discriminating assays against a panel of TAAs [23]. between breast carcinoma patients and healthy subjects) Disis et al. [34] demonstrated by western blot analysis of AAbs to HSP-60 was represented by a speciﬁcity of in 1994 that serum anti-HER2 AAbs are present in 11/20 95.7%, sensitivity of 31.8%, positive predictive value of (55%) patients with breast carcinoma. They conﬁrmed that 89.5%, negative predictive value of 54.9%, and area under the HER2 oncoprotein elicits an immune response and spec- curve (AUC) of 63.7% [31]. Notably, no signiﬁcant relation ulated that the HER2 oncoprotein may be used as a target was found between the frequency of AAbs to HSP-60 and for speciﬁc immunotherapy [34]. In 1997, Disis et al. [35] estrogen receptor (ER), progesterone receptor (PR) and showed by capture enzyme-linked immunosorbent assay Journal of Oncology 7 (ELISA) and veriﬁed by western blot analysis that serum foresee that the newly developed chemiluminescent optical anti-HER2 AAbs, at titers of > or = 1 : 100, were present in ﬁber immunosensor might serve as an eﬃcient tool for early 12/107 (11.2%) early-stage breast carcinoma patients and in diagnosis of breast and ovarian carcinomas [37]. none (0%) of 200 healthy controls (P< .01). The presence of serum anti-HER2 AAbs correlated to overexpression of 7. Autoantibodies to c-myc and c-myb Protein HER2 protein in the patient’s primary tumor. Nine of 44 (20.4%) patients with HER2-positive tumor had serum anti- The myc gene encodes for a transcription factor, c-myc HER2 AAbs, whereas only 3/63 (4.8%) patients with HER2- protein, that is essential for cell growth and proliferation negative tumor had serum anti-HER2 AAbs (P = .03). In and is broadly implicated in tumorigenesis [86–88]. Serum contrast to the previous study, Disis et al. [16, 36]observed anti-c-myc AAbs were detected by ELISA in 12/94 (12.7%) in 2000 that serum anti-HER2 AAbs were present in only patients with newly diagnosed breast carcinoma and 3/40 3/45 (6.6%) advanced-stage breast carcinoma patients. The (7.5%) patients with ductal carcinoma in situ [23]. Positive lower incidence of serum anti-HER2 AAbs in advanced- seroreactivity wasdeﬁnedasanabsorbancevalue greater stage disease compared to early-stage disease suggests that than the mean plus two standard deviations of a normal the humoral immune response to HER2 may have a role in cohort. The sensitivity and speciﬁcity were 13% and 97%, limiting breast carcinoma progression. respectively, for breast carcinoma and 8% and 97%, respec- Lu et al. [1] demonstrated by recombinant ELISA that tively, for ductal carcinoma in situ. It has been concluded AAbs to HER2 protein were present in the sera of 30/225 that measurement of serum AAbs to c-myc protein only is (13%) breast carcinoma patients compared to 10/200 (5%) of little value for screening and early diagnosis of breast healthy controls. It seems that serum AAbs to HER2 have carcinoma; however, AAbs to c-myc may have promising no diagnostic potential when examined alone (unacceptable diagnostic potential when incorporated in AAb assays against high false negative rate); however, they may possibly have apanel of TAAs [23]. diagnostic potential when incorporated in AAb assays to a The Myb gene encodes for a transcription factor, c-myb panel of TAAs. protein, that is required during multiple stages of T cell development and is involved in cell cycle G1/S transition and antiapoptosis [89, 90]. Using Western blotting, Sorokine et 6. Autoantibodies to GIPC-1 Protein al. [38] demonstrated that IgG AAbs against c-myb protein were present in the sera of 31/72 (43%) breast carcinoma The protein known as GIPC-1, a member of a family of PDZ- patients compared to 12/49 (24.5%) healthy controls (P = domain conserved proteins, is involved in regulation of G- .036). No signiﬁcant correlation was observed between the protein signaling and is upregulated in breast and ovarian presence of circulating AAbs to c-myb protein and the carcinomas [37, 83–85]. With use of 27.B1 and 27.F7 human expression of the c-myb gene in breast tumors. monoclonal antibody speciﬁc to GIPC-1 protein, Yavelsky et al. [83] demonstrated a positive immunnohistochemical staining for GIPC-1, respectively, in 24/25 (96%) and 11/23 8. Autoantibodies to NY-ESO-1 Protein (48%) breast ductal carcinomas, 9/10 (90%) and 8/15 (53%) breast lobular carcinomas, 0/4 and 0/4 breast ductal Cancer-testis (CT) antigens are encoded by a group of carcinomas in situ, 0/4 and 0/4 breast lobular carcinomas genes predominantly expressed in human germline cells. in situ, 0/4 and 0/4 breast ﬁbroadenomas, and 0/4 and They are downregulated in somatic adult tissues but may 0/4 breast hyperplasias. GIPC-1 staining with 27.B1 and become aberrantly expressed in several types of cancers. CT 27.F7 antibodies was positive only in invasive breast carci- antigens mapping to chromosome X are referred to as CT-X nomas (27.B1 displayed a higher reactivity rate than 27.F1) antigens and distinguished from non-X CT antigens located whereas GIPC-1 staining with 27.B1 and 27.F7 antibodies on autosomes [91, 92]. The CT-X antigens represent more was negative in in situ and benign tumors (P< .001). The than half of all CT antigens and their expression is frequently authors [83] assume that GIPC-1 protein is cancer-associated associated with a poorer outcome and higher grade and and hypothesize that serum AAbs to GIPC-1 may possibly advanced stage tumors [91, 92]. Only few studies have serve as a marker for invasive breast carcinoma. With use explored the presence of CT antigens (NY-ESO-1 and/or of a novel technique of chemiluminescent optical ﬁber MAGE-A) in breast carcinoma rendering contradictory immunoassay (the instrument is called chemiluminescent results [93–95]. Interestingly, recent studies showed elevated optical ﬁber immunosensor), Salama et al. [37]testedsera expression of the CT antigens, NY-ESO-1 and MAGE-A, from 22 breast carcinoma patients, 11 epithelial ovarian in triple-negative (ER-negative, PR-negative, and HER2- carcinoma patients, and healthy controls for the presence of negative) breast carcinomas [91, 96]. IgM anti-GIPC-1 AAbs. The chemiluminescent optical ﬁber Serum anti-NY-ESO-1 AAbs were identiﬁed by ELISA immunosensor detected 77% and 54% anti-GIPC-1 AAbs in 25/94 (26.6%) patients with newly diagnosed breast car- positive sera within breast and ovarian carcinoma patients, cinoma and 3/40 (7.5%) patients with ductal carcinoma in respectively, as compared to ELISA, which only detected 27% situ [23]. Positive seroreactivity was deﬁned as an absorbance and 18%, respectively [37]. The authors conclude that the value greater than the mean plus two standard deviations of chemiluminescent optical ﬁber immunoassay is an eﬃcient a normal cohort. The sensitivity and speciﬁcity were 26% technique for prompt detection of AAbs to TAAs and, thus, and 94%, respectively, for breast carcinoma, and 8% and 8 Journal of Oncology 94%, respectively, for ductal carcinoma in situ. It has been the incidence of naturally occurring serum antiendostatin concluded that measurement of serum AAbs to NY-ESO-1 AAbs and extent of disease. Serum antiendostatin AAbs protein only is of little value for screening and early diagnosis were detected in 4/24 (16%) healthy women, 24/36 (66.6%) of breast carcinoma; however, AAbs to NY-ESO-1 may have patients with localized breast carcinoma, and 25/59 (42.4%) promising diagnostic potential when incorporated in AAb patients with metastatic breast carcinoma. Diﬀerences were assays against a panel of TAAs [23]. statistically signiﬁcant between all breast carcinoma patients and healthy controls (P< .0001) and between localized and metastatic breast carcinoma patients (P = .03). The 9. Autoantibodies to BRCA Protein detection of serum antiendostatin AAbs was correlated to better survival in metastatic breast carcinoma patients. The The wild-type BRCA genes, BRCA1 (located on chromosome median survival time of the 25 patients with detectable 17q21) and BRCA2 (located on chromosome 13q12-13), serum anti-edostatin AAbs was 20 months compared to 7 are tumor-suppressor genes. The 185delAG and 5382insC months for the other 34 patients (P = .03). There was no mutations in the BRCA1 gene and the 6174delT mutation correlation to circulating levels of endostatin. The authors in the BRCA2 gene have been found to be signiﬁcantly more [39] have concluded that a natural immune reaction against commonamong AshkenaziJews(Jews of easternEuropean endostatin can occur in breast cancer patients. The incidence ancestry) (1 in 40, 2.5%) in comparison to the general of serum antiendostatin AAbs is higher in patients with population (1 in 800 to 1in 300, 0.12%–0.33%). Carriers of localized disease and is associated with a better prognosis these “Ashkenazi mutations” have a signiﬁcantly increased in patients with metastatic disease. It has been suggested lifetime risk of breast carcinoma (about 50%), ovarian that the reaction of anti-edostatin AAbs against tumor carcinoma and other carcinomas as compared to noncarriers blood vessels may slow down tumor progression in breast [97]. carcinoma patients and partially explain the better survival AAbs to BRCA1 and BRCA2 protein were identiﬁed of serum antiendostatin AAb-positive patients [39]. by ELISA in the sera of 8/94 (8.5%) and 32/94 (34%) invasive breast carcinoma patients, respectively, and 1/40 (2.5%) and 9/40 (22.5%) ductal carcinoma in situ patients, 11. Autoantibodies to Lipophilin B Protein respectively [23]. Positive seroreactivity was deﬁned as an absorbance value greater than the mean plus two standard Lipophilins and mammaglobins are members of the utero- deviations of a normal cohort. The sensitivity and speciﬁcity globin family, and mammaglobin has been shown to be of evaluating serum anti-BRCA1 AAbs were 8% and 91%, highly breast tissue speciﬁc [101, 102]. More recently, respectively, for invasive breast carcinoma, and 3% and 91%, lipophilin B, which is also present in breast tissue and respectively, for ductal carcinoma in situ. The sensitivity and other tissues, has been identiﬁed as forming a complex speciﬁcity of evaluating serum anti-BRCA2 AAbs were 34% with mammaglobin that is potentially secreted into serum and 92%, respectively, for invasive breast carcinoma, and [103, 104]. 23% and 92%, respectively, for ductal carcinoma in situ.It Carter et al. [40] observed in 2003 that preexisting has been concluded that (1) assessment of serum AAbs to AAbs to lipophilin B peptide are absent in 20 healthy BRCA1 protein alone is of no value for screening and early donor sera and 30 lung carcinoma sera, but present in the sera of 20/74 (27%) breast carcinoma patients overall, and diagnosis of breast carcinoma, (2) serum AAbs to BRCA1 have no diagnostic potential even if incorporated in AAb 13/35 (37.1%) advanced-stage (stage IV) breast carcinoma assays against a panel of TAAs, (3) assessment of serum AAbs patients. This immune response was diﬀerent from that seen to BRCA2 protein alone is of little value for screening and to recombinant mammaglobin and native mammaglobin- early diagnosis of breast carcinoma, and (4) serum AAbs to lipophilin B complex. The authors [40] have suggested that BRCA2 may have, however, promising diagnostic potential the humoral immune responses to lipophilin B may serve as when incorporated in AAb assays against a panel of TAAs a diagnostic indicator, particularly for breast carcinoma. [23]. 12. Autoantibodies to Cyclin Proteins 10. Autoantibodies to Endostatin Protein Cyclins are molecules that control the progression through Endostatin, one of the most potent known natural inhibitors the cell cycle. Cyclin B1 is important in the cell cycle of angiogenesis, is a C-terminal fragment of collagen XVIII, progression from G2-to-M phase and has been shown to be which is highly expressed in the perivascular basement mem- overexpressed in several tumors [41, 105]. Several studies brane of tumor-associated blood vessels [98, 99]. Elevated [3, 106] have shown that serum AAbs to cyclin B1 protein serum levels of endostatin have been found in metastatic can be found in patients with various tumors and might be a cancer patients and have been correlated to the clinical course useful diagnostic marker in combination with AAbs against of the disease in various tumor types [39, 100]. several other tumor antigens. Suzuki et al. [41] examined Bachelot et al. [39] examined in 2006 with use of by ELISA the presence of serum AAbs to cyclin B1 in 120 Western blotting approach the immunoreactivity of serum patients (7 with breast carcinoma, 17 with pancreatic cancer, samples of breast carcinoma patients against recombinant 27 with colon cancer, and 69 with lung cancer) and found human endostatin and found an inverse correlation between that the highest proportion of patients strongly positive Journal of Oncology 9 (absorbance ≥1) for AABs to cyclin B1 was in the breast protein which, unlike other IGFBPs, is not glycosylated and carcinoma group (3/7, 42.8%). A correlation of serum AAbs occurs only in its nonphosphorylated form. to cyclin B1 to higher level of tumor cyclin B1 expression Lu et al. [1] demonstrated by recombinant ELISA the was found. AAbs to cyclin B1 in patients with breast and presence of AAbs to (IGFBP-2) in the sera of 21/142 (15%) colon carcinoma were primarily of the IgG isotype whereas breast carcinoma patients compared to 2/100 (2%) healthy patients with pancreatic and lung carcinoma had in addition controls. Goodell et al. [43]demonstratedbyspeciﬁcally AAbs of the IgA isotype. The authors [41] have speculated designed his-tagged capture ELISA (based on lysate from that anticyclin B1 AAbs may have a role as a serum marker genetically engineered Chinese hamster ovary cells) the for early detection of cancer. presence of AAbs to IGFBP-2 in the sera of 4/80 (5%) Lu et al. [1] demonstrated by recombinant ELISA the breast carcinoma patients, 32/80 (40%) colorectal carcinoma presence of serum AAbs to cyclin D1 in 3/40 (7.5%) patients and 2/200 (1%) healthy controls. These corre- breast carcinoma patients compared to 4/80 (5%) healthy sponded to a signiﬁcant diﬀerence between all carcinoma controls. It seems that AAbs to cyclin D1 protein have no patients and healthy controls (P = .008), between breast diagnostic potential when examined alone; however, they carcinoma patients and healthy controls (P = .032), and may possibly have diagnostic potential when incorporated in between colorectal carcinoma patients and healthy controls autoantibody assays against a panel of TAAs. (P< .001) [43]. The authors concluded that the AAbs to IGFBP-2 assayed by capture ELISA can discriminate between cancer patients and controls [43]. It seems, however, that 13. Autoantibodies to Fibulin Protein AAbs to IGFBP-2 have little value for screening and early diagnosis of breast carcinoma when examined alone. AAbs Fibulin-1(Fbln-1) is a member of an emerging family of to IGFBP-2 may perhaps have diagnostic potential when glycoproteins found in extracellular matrix (ECM) and incorporated in AAb assays against a panel of TAAs. blood and has been observed to inhibit in vitro adhesion and motility of various carcinoma cell lines [107, 108]. Fbln-1 has been implicated as having a role in cancer, especially in breast 15. Autoantibodies to TOPO2α Protein carcinoma, and possible involvement in triggering protective antitumor immune responses [109–112]. Topoisomerase II is a ubiquitous enzyme that regulates DNA With use of SEREX, serum AAbs to the glycoprotein under- and overwinding, and removes knots and tangles Fbln-1 were identiﬁed in 15/20 (75%) breast carcinoma from the genome. Its two homologous isoforms, topoiso- patients compared to 4/20 (25%) healthy controls (P< merase IIα and topoisomerase IIβ, share ∼70% amino acid .0006) [42, 110]. It has been concluded that the SEREX- sequence identity and display similar enzymatic activities. deﬁned molecule Fbln-1 is able to elicit both cellular and Topoisomerase IIα (TOPO2α) is an essential enzyme, and its humoral immune responses in breast carcinoma patients. levels increase dramatically during periods of cell growth. It The ﬁnding that Fbln-1 expression is associated with is tightly associated with mitotic chromosomes and has an improved survival in patients with lymphoid inﬁltrate at the essential role during DNA replication and mitosis [115]. tumor site suggests the possible involvement of Fbln-1 in Lu et al. [1] revealed by recombinant ELISA the presence triggering protective antitumor immune responses [112]. In of AAbs to TOPO2α protein in the sera of 8/115 (7%) addition, it has been suggested that AAbs to Fbln-1 may breast carcinoma patients compared to 4/200 (2%) healthy perhaps be exploited as a tool for early detection of breast controls. It seems that serum AAbs to TOPO2α have no carcinoma [111]. diagnostic potential in breast carcinoma when examined alone; however, they may possibly have diagnostic potential 14. Autoantibodies to Insulin-Like Growth when incorporated in autoantibody assays against a panel of Factor Binding Protein 2 (IGFBP-2) TAAs. The insulin-like growth factors, IGF-1 and IGF-2, the type 1 and type 2 IGF receptors, and the six known IGF binding 16. Autoantibodies to Cathepsin D Protein proteins, IGFBP-1–6, comprise a complex system of peptide hormones, cell surface receptors and circulating factors Primary biological function of enzymatically active cathepsin involved in the regulation of growth, survival and diﬀeren- D is protein degradation in an acidic milieu of lysosomes tiation in a vast number of tissues [113]. The IGFBPs are [116]. Failure of this function resulted in accumulation secretory proteins and possess an 80% sequence homology of lipofuscin in variety of cell types, neurodegeneration, with each other, reserving binding preferences for either IGF- developmental regression, and visual loss. Procathepsin D, 1 or IGF-2 [114]. IGFBPs have been proposed to have the secreted from cancer cells, acts as a mitogen on both following functions: (1) to act as transport carrier proteins cancer and stromal cells and stimulates their proinvasive and of IGFs, (2) to stabilize and prolong the half-lives of IGFs prometastatic properties. Procathepsin D/cathepsin D levels thereby regulating their metabolic clearance, (3) to provide represent an independent prognostic factor in a variety of a means of tissue- and cell- type- speciﬁc localization, and cancers [116]. (4) to directly stimulate or inhibit interactions of the IGFs Using recombinant ELISA, Lu et al. [1]detectedAAbs with their receptors [114]. The IGFBP-2 is a 36 kDa secretory to cathepsin D protein in the sera of 5/100 (5%) breast 10 Journal of Oncology carcinoma patients compared to 3/100 (3%) healthy con- ﬁnding(s) on mammography (BI-RADS category 2) trols. It seems that serum AAbs to cathepstin D have no [122], presence of serum AAbs to breast carcinoma diagnostic potential in breast carcinoma when examined TAAs might lead to a decision to perform immediate alone; however, they may possibly have diagnostic potential additional imaging studies (ultrasound and/or MRI) when incorporated in autoantibody assays against a panel of or, in women with BI-RADS category 2, even an TAAs. immediate breast biopsy to obtain tissue for histo- logical diagnosis rather than to wait one year for the next routine annual screening mammography. 17. Conclusions and Personal Viewpoints On the other hand, in women with negative ﬁndings on mammography (BI-RADS category 1) and in Breast carcinoma is the most common malignancy and women with benign ﬁnding(s) on mammography the most frequent cause of death from cancer in women. (BI-RADS category 2) [122], absence of serum AAbs Traditional diagnostic tools for early detection, namely, man- to breast carcinoma TAAs would support the decision ual breast examination, imaging studies (mammography, to wait one year for the next routine annual screening ultrasound, and MRI), and measurement of serum CA-15-3 mammography. are crippled with insuﬃcient sensitivity and speciﬁcity. The mean sensitivity of mammography has been estimated to be (4) Women with an incomplete mammography assess- 77% (range: 29%–97%) [117–119]. The rate of false-negative ment (BI-RADS category 0) [122] would need mammography has been reported to be 4%–34% [120, 121]. immediate additional imaging evaluation (ultra- Serum AAbs to speciﬁc TAAs are detectable in cancer patients sound and/or MRI) and/or prior mammograms even when the tumor is obscured clinically. Evidently, the for comparison irrespective of the status of serum human immune system recognizes the autologous TAAs as AAbs to breast carcinoma TAAs. Nevertheless, the “nonself ” and makes a humoral immune response very early presence of serumAAbstobreastcarcinoma TAAs in the disease process. Thus, the identiﬁcation of serum AAbs in such women would hasten the assessment by to TAAs could potentially be used as a novel tool for screen- additional imaging studies and might even bring to ing and early diagnosis of breast carcinoma. Nevertheless, it the performance of an immediate breast biopsy to has been shown that measurement of AAbs against a single obtain tissue for histological diagnosis. TAA is of little value and only assessment of AAbs to a tailor-made panel of TAAs may have promising diagnostic potential. The implications of this would be that AAbs to Conﬂict of Interests TAAs would provide a simple blood test for screening and early diagnosis of breast carcinoma. Nevertheless, it must The authors declare no conﬂict of interests. be remembered that measurement of serum AAbs to TAAs for screening and early diagnosis of breast carcinoma is References still investigational and should be carried out along with traditional screening and diagnostic studies. Our personal [1] H. Lu, V. Goodell, and M. L. 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Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2010 Ettie Piura and Benjamin Piura. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8450
eISSN: 1687-8469
DOI: 10.1155/2010/264926
Publisher site: See Article on Publisher Site

Abstract

Hindawi Publishing Corporation Journal of Oncology Volume 2010, Article ID 264926, 14 pages doi:10.1155/2010/264926 Review Article Autoantibodies to Tumor-Associated Antigens in Breast Carcinoma 1 2 Ettie Piura and Benjamin Piura Department of Obstetrics and Gynecology, Sapir Medical Center, Sackler School of Medicine, University of Tel-Aviv, Kfar-Saba 44281, Israel Unit of Gynecologic Oncology, Department of Obstetrics and Gynecology, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel Correspondence should be addressed to Benjamin Piura, piura@bgu.ac.il Received 21 July 2010; Revised 4 September 2010; Accepted 19 October 2010 Academic Editor: Aysegula A. Sahin Copyright © 2010 E. Piura and B. Piura. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identiﬁed in the circulation of patients with cancer. This paper will focus on recent knowledge related to circulating AAbs to TAAs in breast carcinoma. So far, the following TAAs have been identiﬁed to elicit circulating AAbs in breast carcinoma: p53, MUC-1, heat shock proteins (HSP-27, HSP-60, and HSP-90), HER2/neu/c-erb B2, GIPC-1, c-myc, c-myb, cancer-testis antigens (NY-ESO-1), BRCA1, BRCA2, endostatin, lipophilin B, cyclin B1, cyclin D1, ﬁbulin, insulin-like growth factor binding protein 2 (IGFBP-2), topoisomerase II alpha (TOPO2α), and cathepsin D. Measurement of serum AAbs to one speciﬁc TAA only is of little value for screening and early diagnosis of breast carcinoma; however, assessment of AAbs to a panel of TAAs may have promising diagnostic potential. 1. Introduction over 2,000 candidate TAAs in many types of human cancer have been identiﬁed and separated into six categories [5, 8– The development of circulating autoantibodies (AAbs) to 11]: (1) diﬀerentiation antigens (expressed by cancers and tumor-associated antigens (TAAs) has been observed to a restricted subset of normal cells, e.g., tyrosinase, melan- be associated with cancer [1, 2]. Unlike traditional tumor A/MART-1, NY-BR-1, and gp100), (2) mutational antigens markers (e.g., CA-15-3, CA-19-9, CA-125, and CEA), which (e.g., CDK4, β-catenin, caspase-8, and p53), (3) ampliﬁ- are soluble proteins shed by bulky tumors, serum AAbs to cation (overexpression) antigens (e.g., c-erb B2/HER2/neu, TAAs are detectable even when the tumor is very small [2]. NY-C0-58, and p53), (4) splice variant antigens (e.g., NY- Thus, the identiﬁcation of AAbs to TAAs could potentially CO-37/PDZ-45, and ING1), (5) viral antigens (e.g., HPV be used as a novel tool for screening and early diagnosis and EBV), and cancer-testis (CT) antigens (e.g., NY-ESO- of cancer [2–6]. Sahin et al. [7] introduced in 1995 a 1, MAGE-A, and LAGE-1). The humoral immune response method called SEREX (serological analysis of recombinant elicited by TAAs could have two major clinical applications cDNA expression libraries) that has broad applicability to [9]: (1) AAbs to TAAs could represent novel biomarkers the analysis of the humoral immune response to cancer. for cancer diagnosis, prognosis, monitoring, and prediction Originally, they had used mRNA isolated from tumor tissue of response to chemotherapy, (2) TAAs might be used with the assumption that speciﬁc TAAs could be isolated. as targets for immunotherapy of cancer. Notwithstanding, This has turned out to be incorrect, since there is no such eﬀorts to predict cancer based on autoimmunity to either thing as a TAA that is only expressed in tumors. Thus, the an individual TAA or even tailor-made panel of TAAs have SEREX method as described by the original authors has been not yet resulted in serologic biomarkers with deﬁnitive highly modiﬁed and uses nowadays cDNA libraries from a predicting speciﬁcity and sensitivity [12]. It has, however, variety of cell lines and not just from tumor tissues. So far, been shown by some investigators that the use of tailor-made 2 Journal of Oncology panel of TAAs, rather than individual TAAs, enhances the circulating AAbs to speciﬁc breast carcinoma TAAs have been likelihood of detecting cancer-associated AAbs with potential identiﬁed and investigated. In breast carcinoma, like in other diagnostic value [3, 12]. malignancies, the use of tailor-made panel of TAAs, rather In the USA, breast carcinoma is diagnosed in approxi- than individual TAAs, enhances the likelihood of detecting mately 193,000 women and 2,000 men yearly with an age- cancer-associated AAbs with potential diagnostic value. adjusted incidence of 125 new cases/100,000 women/year This paper will review the up-to-date knowledge related and 1 new case/100,000 men/year, and it causes approxi- to AAbs against individual TAAs in breast carcinoma. Table 1 mately 41,000 deaths (40,500 women and 500 men) each shows the frequency of identiﬁed AAbs to breast carcinoma year [13, 14]. Breast carcinoma is the ﬁrst most common TAAs. cancer among women (27% of all cancers in women) and the second most common cause of death from cancer, after lung carcinoma, in women (15% of all cancer deaths in women) 2. Autoantibodies to p53 Protein [13]. The National Cancer Institute (NCI) has estimated that 12.7% (1/8) of women born today in the USA will be The wild-type p53 gene is a tumor suppressor gene located diagnosed with breast carcinoma at some time in their lives on chromosome 17p13 and encodes a 53-kDa nuclear phos- [15]. Theﬁve-yearsurvivalrateoverall of womenwithbreast phoprotein that normally acts as a guardian of the integrity carcinoma in the USA is about 90% [14]. of the genome [27, 44, 45]. Mutations in p53 are the most Worldwide, breast carcinoma is by far the most frequent common genetic changes found in human malignancies cancer among women with an estimated 1.38 million new and the mutational status of p53 is prognostic in many cases diagnosed in 2008 (23% of all malignancies in women) malignancies [46]. In breast carcinoma, p53 mutations have and ranks second overall (10.9%), after lung carcinoma, of been shown to be associated with worse overall and disease- all malignancies in both sexes [16]. The estimated incidence free survival, independent of other risk factors, and have of breast carcinoma in 2008 worldwide has been 39 new been implicated in resistance to anticancer therapies [47, cases/100,000 women. The incidence has been estimated to 48]. Missense point mutations, which represent more than vary from 19.3 in Eastern Africa to 89.9 in Western Europe, 85% of gene abnormalities, lead to a conformational change and is high (greater than 80) in developed countries (except which stabilizes the p53 protein and allows it to accumulate Japan) and low (less than 40) in most of the developing in the nucleus to relatively high levels [27, 44, 45, 49–51]. countries [16]. Breast carcinoma has been estimated to cause Accumulation of the mutant p53 in tumor cells can elicit 458,000 deaths in 2008 worldwide (13.7% of all cancer a humoral immune response leading to the production of deaths in women and 6% of all cancer deaths in both anti-p53 AAbs [27]. Initially, it was thought that only tumors sexes). The estimated mortality from breast carcinoma in with missense p53 mutations resulting in p53 overexpression 2008 worldwide has been 12.5 deaths/100,000 women. Breast can elicit anti-p53 AAbs [27, 52–54]. Later on, however, carcinoma is the most frequent cause of death from cancer in anti-p53 AAbs have also been detected in sera from patients women worldwide and the ﬁfth cause of death from cancer, with tumors lacking p53 overexpression. Induction of anti- after lung, stomach, liver, and colorectal carcinoma, in both p53 AAbs in these patients might be due to the unusual sexes [16]. presentation of large amounts of wild-type p53 from necrotic Current screening modalities for breast carcinoma diag- large tumors or metastases [27, 55]. Recently, it has been nosis include mammography, ultrasound (US), and mag- shown that anti-p53 AAbs are directed against immunodom- netic resonance imaging (MRI); however, there is still an inant epitopes localized in the amino and carboxy terminal urgent need to develop an alternative modality of screening ends of the p53-protein, unrelated to the mutational hot for earlier diagnosis [17]. The use of serum-soluble tumor spot [27, 51, 56–58]. Epithelial ovarian carcinomas have antigens, such as CA-15-3 glycoprotein, as biomarkers for been regarded as a tumor entity associated with the highest detection of breast carcinoma has been limited by their frequency (13%–46%) of circulating anti-p53 AAbs [59]; insuﬃcient speciﬁcity and sensitivity, particularly for organ nevertheless, breast carcinomas are also associated with a conﬁned early-stage disease. Consequently, CA-15-3 is not considerable incidence (2.8%–47.5%) of serum anti-p53 recommended for use in the screening or detection of breast AAbs. Thus, breast carcinomas, alongside epithelial ovarian carcinoma [18–21]. This is in part due to the elevation of CA- carcinomas, are among the most immunogenic malignancies 15-3 in benign conditions including breast, liver, and kidney inducing anti-p53 AAbs response. Indeed, while mutation disorders and other cancers [22]. Thus, there is a need to of p53 appears a seminal event in carcinogenesis and is discover novel biomarkers, such as AAbs to speciﬁc breast present in ∼30% of breast carcinoma patients, it is still carcinoma TAAs, for screening, early diagnosis, prediction unclear why only a subset of p53 mutation-positive breast of prognosis, and monitoring of treatment. There is also carcinoma patients (∼50%) generates anti-p53 AAbs [27]. It a need to develop new therapeutic approaches, such as has been suggested that only p53 mutations that are localized immunotherapy, for the management of breast carcinoma. in exons 5 and 6 with an altered protein conformation and TheestablishmentofAAbstoTAAsasbiomarkersfor breast that bind to HSP-70 are associated with anti-p53 AAbs [54, carcinoma and the development of successful immunother- 58]. Further studies, however, have demonstrated that other apeutic strategies require the identiﬁcation and characteri- factors contribute to the humoral immune response to p53 zation of immunogenic breast carcinoma TAAs that will be protein and suggested that the capacity to elicit a humoral recognized by the host immune system. Thus far, only few immune response is linked to the biological background Journal of Oncology 3 Table 1: Frequency of identiﬁed circulating AAbs to TAAs in breast carcinoma. AAbtoTAA Positive Total % Comment Reference Promising diagnostic potential when 22 94 23.4 p53 [23] incorporated in AAb assays to a panel of a a 6 40 15.0 TAAs p53 [24] 11 24 45.8 Association with higher risk for relapse. Correlation to higher stage, lymph node p53 [25] 31 144 21.5 metastasis, negative ER, positive c-erbB-2 and worse survival. Correlated neither with p53 cytosolic p53 8 101 7.9 [26] assay nor with prognostic factors. Promising diagnostic potential when p53 22 220 10 incorporated in AAb assays to a panel of [1] TAAs Summary of 15 studies (1979–1999). Frequency of AAbs: 2.8%–47.5%. Few p53 [27] 296 2006 14.7 studies showed association with high grade and poor survival. Promising diagnostic potential when 19 94 20.2 MUC1 incorporated in AAb assays to a panel of [23] a a 9 40 22.5 TAAs. No correlation to circulating mucin levels MUC1 [28] 224 8.3 or stage of disease. Inverse correlation to extent of disease. b b b 36 140 25.7 MUC1 [29] Suggested role in protection against c c c 11 61 18.0 disease progression. Promising diagnostic potential when MUC1 20 100 20 incorporated in AAb assays to a panel of [1] TAAs. HSP-27 [30] 219 579 37.8 Association with improved survival. 18 58 31 HSP-60 Promising diagnostic potential. [31] a a a 16 49 33 Correlation to extent of disease. HSP-90 46 125 36.8 [32] Promising diagnostic potential. HSP-90 135 214 63.1 Association with higher mortality rate. [33] Promising diagnostic potential when 16 94 17.0 HER2/neu incorporated in autoantibody assays [23] a a 5 40 12.5 against a panel of TAAs. HER2/neu oncoprotein elicits an HER2/neu [34] 11 20 55 immune response and may be used as a target for speciﬁc immunotherapy. 12 107 11.2 Correlation to positive HER2/neu status b d d d HER2/neu 9 44 20.4 [35] in the primary tumor (P = .03). e e 3 63 4.8 Incidence is lower in advanced-stage disease compared to early-stage disease. HER2/neu [36] 345 6.6 Suggested role in limiting disease progression. Promising diagnostic potential when HER2/neu 30 225 13 incorporated in AAb assays to a panel of [1] TAAs. GIPC-1 [37] 17 22 77 Promising diagnostic potential. Promising diagnostic potential when 12 94 12.7 c-myc [23] incorporated in autoantibody assays a a 3 40 7.5 against a panel of TAAs No correlation to c-myb status in the c-myb [38] 31 72 43 primary tumor. 4 Journal of Oncology Table 1: Continued. AAbtoTAA Positive Total % Comment Reference Promising diagnostic potential when 25 94 26.6 NY-ESO-1/ LAGE-1 [23] incorporated in autoantibody assays a a 3 40 7.5 against a panel of TAAs No diagnostic potential, even if 8 94 8.5 BRCA1 [23] incorporated in autoantibody assays a a a 1 40 2.5 against a panel of TAAs Promising diagnostic potential when 32 94 34.0 BRCA2 incorporated in autoantibody assays [23] a a 9 40 22.5 against a panel of TAAs Inverse correlation to extent of disease. b b b 24 36 66.6 No correlation to circulating levels of Endostatin [39] c c c 25 59 42.4 endostatin. Association with better prognosis in advanced-stage disease. 20 74 27.0 Correlation to extent of disease. Lipophilin B [40] c c c 13 35 37.1 Promising diagnostic potential. Cyclin D1 3 40 7.5 Questionable diagnostic potential [1] Correlation to higher level of tumor Cyclin B1 3 7 42.8 cyclin B1 expression. Questionable [41] diagnostic potential. Fibulin [42] 15 20 75 Promising diagnostic potential. IGFBP2 [1] 21 142 15 Questionable diagnostic potential IGFBP2 [43] 4 80 5 Questionable diagnostic potential TOPO2α [1] 8 115 7 Questionable diagnostic potential Cathepsin D [1] 5 100 5 Questionable diagnostic potential Ductal carcinoma in situ (DCIS). Early-stage disease. Advanced-stage disease. HER2/neu-positive tumor. HER-2/neu-negative tumor. −4 of the patients [27, 52]. It is possible that for an identical controls (P< 10 )[27]. Since serum anti-p53 AAbs mutation, the humoral immune response is dependent on are truly rare in the normal population, the speciﬁcity of the speciﬁc combination of MHC class I and II molecules this assay for the detection of breast carcinoma has been expressed by each individual [27]. estimated to attain 95%. Nevertheless, since anti-p53 AAbs were present on the average in the sera of only 15% of Dalifard et al. [26] demonstrated by ELISA in 1999 that breast carcinoma patients, the sensitivity of this assay for the anti-p53 AAbs were present in the sera of 8/101 (7.9%) detection of breast carcinoma has been estimated to reach patients with breast carcinoma. The presence of serum anti- only 30% [27]. Five studies [58, 60, 63, 65, 67] indicated p53 AAbs correlated neither with p53 cytosolic assay nor with that serum anti-p53 AAbs are found in patients with tumors prognostic factors. The authors concluded that serum anti- that have high grades and/or that are negative for steroid p53 AAb assay is not useful for the selection of patient groups with poor prognosis [26]. hormone receptors, two clinical parameters known to be associated with p53 mutations and bad prognosis. Two Soussi [27] surveyed the literature from 1979 through studies [67, 68] found an association between serum anti- 1999 on anti-p53 AAbs in the sera of patients with various p53 AAbs and short survival whereas one study [71] did types of cancer. Serum anti-p53 AAbs were present in not ﬁnd any association, and another study [66]found an 1600/9489 (16.8%) patients with diﬀerent malignancies and −4 association with good survival. in 35/2404 (1.4%) healthy controls (P< 10 ). Fifteen studies [52, 54, 58, 60–71] examined anti-p53 AAbs in the Regele et al. [24] demonstrated by ELISA in 2003 that sera of breast carcinoma patients. The frequency of anti- serum anti-p53 AAbs were present in 11/24 (45.8%) patients p53 AAbs in the sera of breast carcinoma patients ranged at initial diagnosis of breast carcinoma. In seven of these 11 patients, therapy was paralleled by decreasing anti-p53 AAb in these studies from 2.8% to 47.5%. Overall, the presence of anti-p53 AAbs was demonstrated in the sera of 296/2006 titers; in four, relapse was preceded by an increase of the titer. (14.7%) breast carcinoma patients [27]. χ test showed that Two patients, who initially tested negative, seroconverted the frequency of anti-p53 AAbs was signiﬁcantly higher in to anti-p53 AAb positivity upon relapse. The authors [24] the sera of breast carcinoma patients compared to healthy concluded that monitoring of serum anti-p53 AAbs during Journal of Oncology 5 followup can be informative about the clinical course of the 1/10 (10%) colon carcinoma patients. Overall, the presence disease and the development of breast carcinoma relapse can or absence of serum anti-MUC1 AAbs did not correlate be preceded by an increase of serum anti-p53 AAb titer. with the levels of circulating mucin or stage of disease [28]. Gao et al. [25] showed by ELISA in 2005 that serum von Mensdorﬀ-Pouilly et al. [29] demonstrated by sandwich anti-p53 AAbs were present in 31/144 (21.5%) patients with enzyme-linked immunoassay in 1996 that anti-MUC1 AAbs breast carcinoma and 12/242 (4.9%) healthy controls. The were present in the sera of 2/96 (2.1%) healthy controls, presence of serum anti-p53 AAbs was associated with several 15/40 (37.5%) patients with benign breast tumor, 36/140 poor prognostic factors including higher clinical stage (P = (25.7%) patients with early-stage breast carcinoma and .0233), lymph nodes metastasis (P = .0033), negative ER 11/61 (18%) patients with advanced-stage breast carcinoma. expression (P = .0250) and positive HER2/c-erbB-2 status Serum anti-MUC1 AAbs were elevated in 24/74 (32.4%) (P = .0227). There was also a strong correlation between node-negative patients and in 12/59 (20.3%) node-positive serum anti-p53 AAbs and tumor immunohistochemical patients andabsolutevalueswerehigherinnode-negative positivity for p53 (P< .0001). The authors [25] speculated patients (P = .0168). There was an inverse correlation that serum anti-p53 AAbs could serve as a useful and between positivity for serum anti-MUC1 AAbs and extent convenient marker for the detection and prognosis of breast of disease; while 3/6 (50%) patients with a carcinoma in carcinoma. situ were positive, only 1/15 (6.7%) patients with more Chapman et al. [23] showed by ELISA in 2007 that than ﬁve nodes involved had elevated levels of anti-MUC1 preoperative serum anti-p53 AAbs were present in 22/94 AAbs. All seven patients with distant metastases at ﬁrst (23.4%) patients with newly diagnosed breast carcinoma diagnosis were anti-MUC1 AAb-negative. Twenty-eight of and 6/40 (15%) patients with ductal carcinoma in situ. 133 patients had a recurrence during followup; 23 (82%) of Positive seroreactivity was deﬁned as an absorbance value these 28 patients were anti-MUC1 AAb-negative at the time greater than the mean plus two standard deviations of a of ﬁrst diagnosis. The 5-year survival of 13 patients who had normal cohort. The sensitivity and speciﬁcity were 24% and elevated pretreatment serum levels of CA-15-3 (>30 U/mL) 96%, respectively, for breast carcinoma, and 15% and 96%, and were anti-MUC1 AAb-positive was better than the 5- respectively, for ductal carcinoma in situ. The authors [23] year survival of 41 patients who had elevated pretreatment concluded that measurement of serum AAbs to p53 protein serum levels of CA-15-3 and were anti-MUC1 AAb-negative only is of little value for screening and early diagnosis of (100% versus 71%, P = .0457). The authors [29]suggested breast carcinoma; however, AAbs to p53 may have promising that a natural humoral immune response to MUC1 seems diagnostic potential when incorporated in AAb assays against to protect against disease progression, while lack of immune apanel of TAAs. reaction, or immune tolerance developing in the course of Lu et al. [1] demonstrated with ELISA in 2008 that AAbs disease, could be an additional risk factor more frequently to p53 protein were present in the sera of 22/220 (10%) associated with an unfavorable outcome. breast carcinoma patients compared to 2/200 (1%) healthy Chapman et al. [23] showed by ELISA in 2007 that serum controls. It has been concluded that AAbs to p53 have no anti-MUC1 AAbs were present in 19/94 (20.2%) patients diagnostic potential when examined alone; however, they with newly diagnosed breast carcinoma and 10/40 (25%) may possibly have diagnostic potential when incorporated in patients with ductal carcinoma in situ. Positive seroreactivity AAB assays to a panel of TAAs. wasdeﬁnedasanabsorbancevalue greaterthanthe mean plus two standard deviations of a normal cohort. The sensitivity and speciﬁcity were 20% and 98%, respectively, for breast carcinoma, and 23% and 98%, respectively, for 3. Autoantibodies to MUC1 Protein ductal carcinoma in situ. The authors [23] concluded that Polymorphic epithelial mucin (PEM, MUC1), a human measurement of serum AAbs to MUC1 protein only is mucin family member, is a high-molecular-weight (over of little value for screening and early diagnosis of breast 400 kDa) transmembrane glycoprotein. It is expressed in a carcinoma; however, AAbs to MUC1 may have promising hyperglycosylated form and low levels by many types of diagnostic potential when incorporated in AAb assays against normal epithelial cells and in a hypoglycosylated form and apanel of TAAs. Lu at al. [1] observed an increased AAb response to p53, high levels by most epithelial adenocarcinomas including breast and ovarian carcinoma [72, 73]. About one-quarter of HER-2, MUC1, topoisomerase II alpha (TOPO2α), insulin- breast and ovarian carcinoma patients have circulating AAbs like growth factor binding protein 2 (IGFBP2), cyclin D1, and Cathepsin D in breast carcinoma patients. Nonetheless, to MUC1, either free or bound to immune complexes. While the presence of these immune complexes has prognostic the most frequently encountered AAb response was directed signiﬁcance in cancer patients, the signiﬁcance of free AAbs against MUC1 protein, which was detected in 20/100 (20%) to MUC1 is less clear [74]. AAbs to MUC1 have been breast carcinoma patients compared to 3/100 (3%) healthy described and correlated with a more favorable prognosis; controls [1]. Obviously, serum AAb-assay against MUC1 protein only thus, it seems that risk for breast carcinoma might be reduced by preexisting MUC1-speciﬁc immunity [75, 76]. is of little value for screening and early diagnosis of breast Using ELISA, Kotera et al. [28] demonstrated in 1994 that carcinoma; however, AAbs to MUC1 may have promising diagnostic potential when incorporated in AAb assays against anti-MUC1 AAbs were present in the sera of 2/24 (8.3%) breast carcinoma, 2/12 (16.7%) pancreatic carcinoma, and a panel of TAAs. Moreover, there is support for the notion 6 Journal of Oncology that preexisting AAbs to MUC1 may reduce the risk of HER-2 status [31]. It seems that measuring AAbs to HSP- developing breast carcinoma and presence of AAbs to MUC1 60 has promising diagnostic potential for early detection in breast carcinoma is correlated with a more favorable of breast carcinoma; however, this is still inconclusive and prognosis. further studies are needed. Conroy et al. [32] demonstrated by ELISA in 1995 that serum AAbs to HSP-90 were present in 46/125 (36.8%) breast carcinoma patients. Seropositivity was deﬁned as a value 4. Autoantibodies to Heat-Shock Proteins greater than the mean value observed in normal controls plus three standard deviations. Multivariate analysis indicated Heat-shock proteins (HSPs) are cytoplasmic proteins that act as molecular chaperones for protein molecules in various that the presence of serum AAbs to HSP-90 (P< .04) intracellular processes. They play an important role in and the presence of axillary lymph node invovlement (P< protein-protein interactions, including folding and confor- .001) correlated with the development of metastases [32]. mation and prevention of inappropriate protein aggregation. Moreover, the presence of serum AAbs to HSP-90 correlated They are called heat-shock proteins since they were ﬁrst with the development of metastases even in patients without discovered in cells exposed to high temperatures. How- axillary lymphnodeinvolvement [32]. In 1998, Conroy et ever, their synthesis is also accentuated under other stress al. [33] showed by ELISA that serum AAbs to HSP-90 were present in 135/214 (63.1%) breast carcinoma patients before conditions, such as exposure of the cell to inﬂammation, infection, ischemia, toxins, cytotoxic drugs, and malignant surgery and 127/200 (63.5%) breast carcinoma patients transformation. HSPs have been classiﬁed into families after surgery. Mortality rate from breast carcinoma was greater in women testing positive for AAbs to HSP-90 than according to their molecular weight [77–79]. Overexpression of HSP-27 in breast carcinoma has been those testing negative for AAbs to HSP-90. Although the associated with shorter disease-free survival [30, 80, 81]. diﬀerence between the two groups did not attest statistical Conroy et al. [30] demonstrated by ELISA in 1998 that signiﬁcance, the authors have concluded that there appears to serum AAbs to HSP-27 were present in 219/579 (37.8%) be an association between higher mortality rate from breast carcinoma and presence of serum AAbs to HSP-90 [33]. breast carcinoma patients compared to 1/53 (1/9%) healthy subjects (P< .001). The mortality rate was lower in women with AAbs to HSP-27 than in those who lacked such AAbs (P = .006). Thus, a signiﬁcant association has been 5. Autoantibodies to found between the presence of serum AAbs to HSP-27 and HER2/Neu/c-ErbB2 (p185) Protein improved survival in breast carcinoma patients [30]. HSP-60 is an abundant, highly conserved protein mostly HER2/Neu/ErbB2 is a member of the epidermal growth localized in the mitochondrial matrix. It plays a role in factor receptor (EGFR) family that is ampliﬁed and overex- the regulation of various cellular functions and assists in pressed in 20%–30% of breast carcinomas. HER2-positive mitochondrial protein folding, unfolding, and degradation. breast carcinoma yields a poor patient prognosis due to HSP-60 is involved also in the process of apoptosis and a high incidence of metastases and intrinsic resistance to interacts with proteins implicated in cell cycle regulation endocrine and conventional chemotherapy. Treatments that [31]. With use of ELISA, Desmetz et al. [31] demonstrated target HER2 expression in cancer cells have been shown to the presence of serum AAbs to HSP-60 (seropositivity was be useful strategies to signiﬁcantly reverse the malignancy deﬁned as a value greater than the mean of the normal induced by HER2 overexpression [82]. population plus two standard deviations) in 16/49 (32.6%) Serum anti-HER2 AAbs were detected by ELISA in ductal carcinoma in situ (DCIS) patients and 18/58 (31%) 16/94 (17%) patients with newly diagnosed breast carcinoma early-stage breast carcinoma patients compared to 4/93 and 5/40 (12.5%) patients with ductal carcinoma in situ (4.3%) healthy subjects. This corresponded to a signiﬁcant [23]. Positive seroreactivity was deﬁned as an absorbance diﬀerence between DCIS patients (P< .0001) or early-stage value greater than the mean plus two standard deviations breast carcinoma patients (P< .0001) and healthy controls. of a normal cohort. The sensitivity and speciﬁcity were The frequency of AAbs to HSP-60 was signiﬁcantly higher 18% and 94%, respectively, for breast carcinoma, and 13% in high-grade DCIS patients (11/23, 47.8%) compared to and 94%, respectively, for ductal carcinoma in situ. It has low-grade DCIS patients (5/26, 19.2%) (P = .0188). This been concluded that measurement of serum AAbs to HER2 corresponded to a higher signiﬁcant diﬀerence between high- protein only is of little value for screening and early diagnosis grade DCIS patients and healthy controls (P< .0001) than of breast carcinoma;however,AAbstoHER2may have between low-grade DCIS patients and healthy controls (P = promising diagnostic potential when incorporated in AAb .0233) [31]. The diagnostic performance (discriminating assays against a panel of TAAs [23]. between breast carcinoma patients and healthy subjects) Disis et al. [34] demonstrated by western blot analysis of AAbs to HSP-60 was represented by a speciﬁcity of in 1994 that serum anti-HER2 AAbs are present in 11/20 95.7%, sensitivity of 31.8%, positive predictive value of (55%) patients with breast carcinoma. They conﬁrmed that 89.5%, negative predictive value of 54.9%, and area under the HER2 oncoprotein elicits an immune response and spec- curve (AUC) of 63.7% [31]. Notably, no signiﬁcant relation ulated that the HER2 oncoprotein may be used as a target was found between the frequency of AAbs to HSP-60 and for speciﬁc immunotherapy [34]. In 1997, Disis et al. [35] estrogen receptor (ER), progesterone receptor (PR) and showed by capture enzyme-linked immunosorbent assay Journal of Oncology 7 (ELISA) and veriﬁed by western blot analysis that serum foresee that the newly developed chemiluminescent optical anti-HER2 AAbs, at titers of > or = 1 : 100, were present in ﬁber immunosensor might serve as an eﬃcient tool for early 12/107 (11.2%) early-stage breast carcinoma patients and in diagnosis of breast and ovarian carcinomas [37]. none (0%) of 200 healthy controls (P< .01). The presence of serum anti-HER2 AAbs correlated to overexpression of 7. Autoantibodies to c-myc and c-myb Protein HER2 protein in the patient’s primary tumor. Nine of 44 (20.4%) patients with HER2-positive tumor had serum anti- The myc gene encodes for a transcription factor, c-myc HER2 AAbs, whereas only 3/63 (4.8%) patients with HER2- protein, that is essential for cell growth and proliferation negative tumor had serum anti-HER2 AAbs (P = .03). In and is broadly implicated in tumorigenesis [86–88]. Serum contrast to the previous study, Disis et al. [16, 36]observed anti-c-myc AAbs were detected by ELISA in 12/94 (12.7%) in 2000 that serum anti-HER2 AAbs were present in only patients with newly diagnosed breast carcinoma and 3/40 3/45 (6.6%) advanced-stage breast carcinoma patients. The (7.5%) patients with ductal carcinoma in situ [23]. Positive lower incidence of serum anti-HER2 AAbs in advanced- seroreactivity wasdeﬁnedasanabsorbancevalue greater stage disease compared to early-stage disease suggests that than the mean plus two standard deviations of a normal the humoral immune response to HER2 may have a role in cohort. The sensitivity and speciﬁcity were 13% and 97%, limiting breast carcinoma progression. respectively, for breast carcinoma and 8% and 97%, respec- Lu et al. [1] demonstrated by recombinant ELISA that tively, for ductal carcinoma in situ. It has been concluded AAbs to HER2 protein were present in the sera of 30/225 that measurement of serum AAbs to c-myc protein only is (13%) breast carcinoma patients compared to 10/200 (5%) of little value for screening and early diagnosis of breast healthy controls. It seems that serum AAbs to HER2 have carcinoma; however, AAbs to c-myc may have promising no diagnostic potential when examined alone (unacceptable diagnostic potential when incorporated in AAb assays against high false negative rate); however, they may possibly have apanel of TAAs [23]. diagnostic potential when incorporated in AAb assays to a The Myb gene encodes for a transcription factor, c-myb panel of TAAs. protein, that is required during multiple stages of T cell development and is involved in cell cycle G1/S transition and antiapoptosis [89, 90]. Using Western blotting, Sorokine et 6. Autoantibodies to GIPC-1 Protein al. [38] demonstrated that IgG AAbs against c-myb protein were present in the sera of 31/72 (43%) breast carcinoma The protein known as GIPC-1, a member of a family of PDZ- patients compared to 12/49 (24.5%) healthy controls (P = domain conserved proteins, is involved in regulation of G- .036). No signiﬁcant correlation was observed between the protein signaling and is upregulated in breast and ovarian presence of circulating AAbs to c-myb protein and the carcinomas [37, 83–85]. With use of 27.B1 and 27.F7 human expression of the c-myb gene in breast tumors. monoclonal antibody speciﬁc to GIPC-1 protein, Yavelsky et al. [83] demonstrated a positive immunnohistochemical staining for GIPC-1, respectively, in 24/25 (96%) and 11/23 8. Autoantibodies to NY-ESO-1 Protein (48%) breast ductal carcinomas, 9/10 (90%) and 8/15 (53%) breast lobular carcinomas, 0/4 and 0/4 breast ductal Cancer-testis (CT) antigens are encoded by a group of carcinomas in situ, 0/4 and 0/4 breast lobular carcinomas genes predominantly expressed in human germline cells. in situ, 0/4 and 0/4 breast ﬁbroadenomas, and 0/4 and They are downregulated in somatic adult tissues but may 0/4 breast hyperplasias. GIPC-1 staining with 27.B1 and become aberrantly expressed in several types of cancers. CT 27.F7 antibodies was positive only in invasive breast carci- antigens mapping to chromosome X are referred to as CT-X nomas (27.B1 displayed a higher reactivity rate than 27.F1) antigens and distinguished from non-X CT antigens located whereas GIPC-1 staining with 27.B1 and 27.F7 antibodies on autosomes [91, 92]. The CT-X antigens represent more was negative in in situ and benign tumors (P< .001). The than half of all CT antigens and their expression is frequently authors [83] assume that GIPC-1 protein is cancer-associated associated with a poorer outcome and higher grade and and hypothesize that serum AAbs to GIPC-1 may possibly advanced stage tumors [91, 92]. Only few studies have serve as a marker for invasive breast carcinoma. With use explored the presence of CT antigens (NY-ESO-1 and/or of a novel technique of chemiluminescent optical ﬁber MAGE-A) in breast carcinoma rendering contradictory immunoassay (the instrument is called chemiluminescent results [93–95]. Interestingly, recent studies showed elevated optical ﬁber immunosensor), Salama et al. [37]testedsera expression of the CT antigens, NY-ESO-1 and MAGE-A, from 22 breast carcinoma patients, 11 epithelial ovarian in triple-negative (ER-negative, PR-negative, and HER2- carcinoma patients, and healthy controls for the presence of negative) breast carcinomas [91, 96]. IgM anti-GIPC-1 AAbs. The chemiluminescent optical ﬁber Serum anti-NY-ESO-1 AAbs were identiﬁed by ELISA immunosensor detected 77% and 54% anti-GIPC-1 AAbs in 25/94 (26.6%) patients with newly diagnosed breast car- positive sera within breast and ovarian carcinoma patients, cinoma and 3/40 (7.5%) patients with ductal carcinoma in respectively, as compared to ELISA, which only detected 27% situ [23]. Positive seroreactivity was deﬁned as an absorbance and 18%, respectively [37]. The authors conclude that the value greater than the mean plus two standard deviations of chemiluminescent optical ﬁber immunoassay is an eﬃcient a normal cohort. The sensitivity and speciﬁcity were 26% technique for prompt detection of AAbs to TAAs and, thus, and 94%, respectively, for breast carcinoma, and 8% and 8 Journal of Oncology 94%, respectively, for ductal carcinoma in situ. It has been the incidence of naturally occurring serum antiendostatin concluded that measurement of serum AAbs to NY-ESO-1 AAbs and extent of disease. Serum antiendostatin AAbs protein only is of little value for screening and early diagnosis were detected in 4/24 (16%) healthy women, 24/36 (66.6%) of breast carcinoma; however, AAbs to NY-ESO-1 may have patients with localized breast carcinoma, and 25/59 (42.4%) promising diagnostic potential when incorporated in AAb patients with metastatic breast carcinoma. Diﬀerences were assays against a panel of TAAs [23]. statistically signiﬁcant between all breast carcinoma patients and healthy controls (P< .0001) and between localized and metastatic breast carcinoma patients (P = .03). The 9. Autoantibodies to BRCA Protein detection of serum antiendostatin AAbs was correlated to better survival in metastatic breast carcinoma patients. The The wild-type BRCA genes, BRCA1 (located on chromosome median survival time of the 25 patients with detectable 17q21) and BRCA2 (located on chromosome 13q12-13), serum anti-edostatin AAbs was 20 months compared to 7 are tumor-suppressor genes. The 185delAG and 5382insC months for the other 34 patients (P = .03). There was no mutations in the BRCA1 gene and the 6174delT mutation correlation to circulating levels of endostatin. The authors in the BRCA2 gene have been found to be signiﬁcantly more [39] have concluded that a natural immune reaction against commonamong AshkenaziJews(Jews of easternEuropean endostatin can occur in breast cancer patients. The incidence ancestry) (1 in 40, 2.5%) in comparison to the general of serum antiendostatin AAbs is higher in patients with population (1 in 800 to 1in 300, 0.12%–0.33%). Carriers of localized disease and is associated with a better prognosis these “Ashkenazi mutations” have a signiﬁcantly increased in patients with metastatic disease. It has been suggested lifetime risk of breast carcinoma (about 50%), ovarian that the reaction of anti-edostatin AAbs against tumor carcinoma and other carcinomas as compared to noncarriers blood vessels may slow down tumor progression in breast [97]. carcinoma patients and partially explain the better survival AAbs to BRCA1 and BRCA2 protein were identiﬁed of serum antiendostatin AAb-positive patients [39]. by ELISA in the sera of 8/94 (8.5%) and 32/94 (34%) invasive breast carcinoma patients, respectively, and 1/40 (2.5%) and 9/40 (22.5%) ductal carcinoma in situ patients, 11. Autoantibodies to Lipophilin B Protein respectively [23]. Positive seroreactivity was deﬁned as an absorbance value greater than the mean plus two standard Lipophilins and mammaglobins are members of the utero- deviations of a normal cohort. The sensitivity and speciﬁcity globin family, and mammaglobin has been shown to be of evaluating serum anti-BRCA1 AAbs were 8% and 91%, highly breast tissue speciﬁc [101, 102]. More recently, respectively, for invasive breast carcinoma, and 3% and 91%, lipophilin B, which is also present in breast tissue and respectively, for ductal carcinoma in situ. The sensitivity and other tissues, has been identiﬁed as forming a complex speciﬁcity of evaluating serum anti-BRCA2 AAbs were 34% with mammaglobin that is potentially secreted into serum and 92%, respectively, for invasive breast carcinoma, and [103, 104]. 23% and 92%, respectively, for ductal carcinoma in situ.It Carter et al. [40] observed in 2003 that preexisting has been concluded that (1) assessment of serum AAbs to AAbs to lipophilin B peptide are absent in 20 healthy BRCA1 protein alone is of no value for screening and early donor sera and 30 lung carcinoma sera, but present in the sera of 20/74 (27%) breast carcinoma patients overall, and diagnosis of breast carcinoma, (2) serum AAbs to BRCA1 have no diagnostic potential even if incorporated in AAb 13/35 (37.1%) advanced-stage (stage IV) breast carcinoma assays against a panel of TAAs, (3) assessment of serum AAbs patients. This immune response was diﬀerent from that seen to BRCA2 protein alone is of little value for screening and to recombinant mammaglobin and native mammaglobin- early diagnosis of breast carcinoma, and (4) serum AAbs to lipophilin B complex. The authors [40] have suggested that BRCA2 may have, however, promising diagnostic potential the humoral immune responses to lipophilin B may serve as when incorporated in AAb assays against a panel of TAAs a diagnostic indicator, particularly for breast carcinoma. [23]. 12. Autoantibodies to Cyclin Proteins 10. Autoantibodies to Endostatin Protein Cyclins are molecules that control the progression through Endostatin, one of the most potent known natural inhibitors the cell cycle. Cyclin B1 is important in the cell cycle of angiogenesis, is a C-terminal fragment of collagen XVIII, progression from G2-to-M phase and has been shown to be which is highly expressed in the perivascular basement mem- overexpressed in several tumors [41, 105]. Several studies brane of tumor-associated blood vessels [98, 99]. Elevated [3, 106] have shown that serum AAbs to cyclin B1 protein serum levels of endostatin have been found in metastatic can be found in patients with various tumors and might be a cancer patients and have been correlated to the clinical course useful diagnostic marker in combination with AAbs against of the disease in various tumor types [39, 100]. several other tumor antigens. Suzuki et al. [41] examined Bachelot et al. [39] examined in 2006 with use of by ELISA the presence of serum AAbs to cyclin B1 in 120 Western blotting approach the immunoreactivity of serum patients (7 with breast carcinoma, 17 with pancreatic cancer, samples of breast carcinoma patients against recombinant 27 with colon cancer, and 69 with lung cancer) and found human endostatin and found an inverse correlation between that the highest proportion of patients strongly positive Journal of Oncology 9 (absorbance ≥1) for AABs to cyclin B1 was in the breast protein which, unlike other IGFBPs, is not glycosylated and carcinoma group (3/7, 42.8%). A correlation of serum AAbs occurs only in its nonphosphorylated form. to cyclin B1 to higher level of tumor cyclin B1 expression Lu et al. [1] demonstrated by recombinant ELISA the was found. AAbs to cyclin B1 in patients with breast and presence of AAbs to (IGFBP-2) in the sera of 21/142 (15%) colon carcinoma were primarily of the IgG isotype whereas breast carcinoma patients compared to 2/100 (2%) healthy patients with pancreatic and lung carcinoma had in addition controls. Goodell et al. [43]demonstratedbyspeciﬁcally AAbs of the IgA isotype. The authors [41] have speculated designed his-tagged capture ELISA (based on lysate from that anticyclin B1 AAbs may have a role as a serum marker genetically engineered Chinese hamster ovary cells) the for early detection of cancer. presence of AAbs to IGFBP-2 in the sera of 4/80 (5%) Lu et al. [1] demonstrated by recombinant ELISA the breast carcinoma patients, 32/80 (40%) colorectal carcinoma presence of serum AAbs to cyclin D1 in 3/40 (7.5%) patients and 2/200 (1%) healthy controls. These corre- breast carcinoma patients compared to 4/80 (5%) healthy sponded to a signiﬁcant diﬀerence between all carcinoma controls. It seems that AAbs to cyclin D1 protein have no patients and healthy controls (P = .008), between breast diagnostic potential when examined alone; however, they carcinoma patients and healthy controls (P = .032), and may possibly have diagnostic potential when incorporated in between colorectal carcinoma patients and healthy controls autoantibody assays against a panel of TAAs. (P< .001) [43]. The authors concluded that the AAbs to IGFBP-2 assayed by capture ELISA can discriminate between cancer patients and controls [43]. It seems, however, that 13. Autoantibodies to Fibulin Protein AAbs to IGFBP-2 have little value for screening and early diagnosis of breast carcinoma when examined alone. AAbs Fibulin-1(Fbln-1) is a member of an emerging family of to IGFBP-2 may perhaps have diagnostic potential when glycoproteins found in extracellular matrix (ECM) and incorporated in AAb assays against a panel of TAAs. blood and has been observed to inhibit in vitro adhesion and motility of various carcinoma cell lines [107, 108]. Fbln-1 has been implicated as having a role in cancer, especially in breast 15. Autoantibodies to TOPO2α Protein carcinoma, and possible involvement in triggering protective antitumor immune responses [109–112]. Topoisomerase II is a ubiquitous enzyme that regulates DNA With use of SEREX, serum AAbs to the glycoprotein under- and overwinding, and removes knots and tangles Fbln-1 were identiﬁed in 15/20 (75%) breast carcinoma from the genome. Its two homologous isoforms, topoiso- patients compared to 4/20 (25%) healthy controls (P< merase IIα and topoisomerase IIβ, share ∼70% amino acid .0006) [42, 110]. It has been concluded that the SEREX- sequence identity and display similar enzymatic activities. deﬁned molecule Fbln-1 is able to elicit both cellular and Topoisomerase IIα (TOPO2α) is an essential enzyme, and its humoral immune responses in breast carcinoma patients. levels increase dramatically during periods of cell growth. It The ﬁnding that Fbln-1 expression is associated with is tightly associated with mitotic chromosomes and has an improved survival in patients with lymphoid inﬁltrate at the essential role during DNA replication and mitosis [115]. tumor site suggests the possible involvement of Fbln-1 in Lu et al. [1] revealed by recombinant ELISA the presence triggering protective antitumor immune responses [112]. In of AAbs to TOPO2α protein in the sera of 8/115 (7%) addition, it has been suggested that AAbs to Fbln-1 may breast carcinoma patients compared to 4/200 (2%) healthy perhaps be exploited as a tool for early detection of breast controls. It seems that serum AAbs to TOPO2α have no carcinoma [111]. diagnostic potential in breast carcinoma when examined alone; however, they may possibly have diagnostic potential 14. Autoantibodies to Insulin-Like Growth when incorporated in autoantibody assays against a panel of Factor Binding Protein 2 (IGFBP-2) TAAs. The insulin-like growth factors, IGF-1 and IGF-2, the type 1 and type 2 IGF receptors, and the six known IGF binding 16. Autoantibodies to Cathepsin D Protein proteins, IGFBP-1–6, comprise a complex system of peptide hormones, cell surface receptors and circulating factors Primary biological function of enzymatically active cathepsin involved in the regulation of growth, survival and diﬀeren- D is protein degradation in an acidic milieu of lysosomes tiation in a vast number of tissues [113]. The IGFBPs are [116]. Failure of this function resulted in accumulation secretory proteins and possess an 80% sequence homology of lipofuscin in variety of cell types, neurodegeneration, with each other, reserving binding preferences for either IGF- developmental regression, and visual loss. Procathepsin D, 1 or IGF-2 [114]. IGFBPs have been proposed to have the secreted from cancer cells, acts as a mitogen on both following functions: (1) to act as transport carrier proteins cancer and stromal cells and stimulates their proinvasive and of IGFs, (2) to stabilize and prolong the half-lives of IGFs prometastatic properties. Procathepsin D/cathepsin D levels thereby regulating their metabolic clearance, (3) to provide represent an independent prognostic factor in a variety of a means of tissue- and cell- type- speciﬁc localization, and cancers [116]. (4) to directly stimulate or inhibit interactions of the IGFs Using recombinant ELISA, Lu et al. [1]detectedAAbs with their receptors [114]. The IGFBP-2 is a 36 kDa secretory to cathepsin D protein in the sera of 5/100 (5%) breast 10 Journal of Oncology carcinoma patients compared to 3/100 (3%) healthy con- ﬁnding(s) on mammography (BI-RADS category 2) trols. It seems that serum AAbs to cathepstin D have no [122], presence of serum AAbs to breast carcinoma diagnostic potential in breast carcinoma when examined TAAs might lead to a decision to perform immediate alone; however, they may possibly have diagnostic potential additional imaging studies (ultrasound and/or MRI) when incorporated in autoantibody assays against a panel of or, in women with BI-RADS category 2, even an TAAs. immediate breast biopsy to obtain tissue for histo- logical diagnosis rather than to wait one year for the next routine annual screening mammography. 17. Conclusions and Personal Viewpoints On the other hand, in women with negative ﬁndings on mammography (BI-RADS category 1) and in Breast carcinoma is the most common malignancy and women with benign ﬁnding(s) on mammography the most frequent cause of death from cancer in women. (BI-RADS category 2) [122], absence of serum AAbs Traditional diagnostic tools for early detection, namely, man- to breast carcinoma TAAs would support the decision ual breast examination, imaging studies (mammography, to wait one year for the next routine annual screening ultrasound, and MRI), and measurement of serum CA-15-3 mammography. are crippled with insuﬃcient sensitivity and speciﬁcity. The mean sensitivity of mammography has been estimated to be (4) Women with an incomplete mammography assess- 77% (range: 29%–97%) [117–119]. The rate of false-negative ment (BI-RADS category 0) [122] would need mammography has been reported to be 4%–34% [120, 121]. immediate additional imaging evaluation (ultra- Serum AAbs to speciﬁc TAAs are detectable in cancer patients sound and/or MRI) and/or prior mammograms even when the tumor is obscured clinically. Evidently, the for comparison irrespective of the status of serum human immune system recognizes the autologous TAAs as AAbs to breast carcinoma TAAs. Nevertheless, the “nonself ” and makes a humoral immune response very early presence of serumAAbstobreastcarcinoma TAAs in the disease process. Thus, the identiﬁcation of serum AAbs in such women would hasten the assessment by to TAAs could potentially be used as a novel tool for screen- additional imaging studies and might even bring to ing and early diagnosis of breast carcinoma. Nevertheless, it the performance of an immediate breast biopsy to has been shown that measurement of AAbs against a single obtain tissue for histological diagnosis. TAA is of little value and only assessment of AAbs to a tailor-made panel of TAAs may have promising diagnostic potential. The implications of this would be that AAbs to Conﬂict of Interests TAAs would provide a simple blood test for screening and early diagnosis of breast carcinoma. Nevertheless, it must The authors declare no conﬂict of interests. be remembered that measurement of serum AAbs to TAAs for screening and early diagnosis of breast carcinoma is References still investigational and should be carried out along with traditional screening and diagnostic studies. Our personal [1] H. Lu, V. Goodell, and M. L. 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Autoantibodies to Tumor-Associated Antigens in Breast Carcinoma

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Autoantibodies to Tumor-Associated Antigens in Breast Carcinoma

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