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CD133 in Breast Cancer Cells: More than a Stem Cell Marker

CD133 in Breast Cancer Cells: More than a Stem Cell Marker Hindawi Journal of Oncology Volume 2019, Article ID 7512632, 8 pages https://doi.org/10.1155/2019/7512632 Review Article 1 1 1,2 1 Federica Brugnoli, Silvia Grassilli, Yasamin Al-Qassab, Silvano Capitani, and Valeria Bertagnolo Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy College of Medicine, University of Baghdad, Baghdad, Iraq Correspondence should be addressed to Valeria Bertagnolo; bgv@unife.it Received 26 April 2019; Accepted 10 August 2019; Published 16 September 2019 Guest Editor: Chia-Jung Li Copyright © 2019 Federica Brugnoli et al. )is 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. Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in in- dustrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. )e molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors. antigen also characterizes adult tissues, including mammary 1. Introduction gland [6–10]. In normal breast tissue, CD133 is not a stem CD133/prominin 1 (PROM1) is a pentaspan trans- cell marker and plays a role in morphogenesis, regulating membrane single-chain glycoprotein (Figure 1(a)) mainly ductal branching and the ratio of luminal to basal cells [10]. localized into protrusions of cellular plasma membrane and Even though CD133 has been variously associated with particularly in the cholesterol-based lipid microdomains, proliferation, cell survival, and autophagy, in precursors indicative of its involvement in membrane organization [1]. and/or mature cells [11], its exact role is not well defined and Transcription of human CD133 is driven by five tissue- a specific ligand was not discovered. specific promoters, three of which located in CpG islands )e expression of CD133 is deregulated in various solid and partially regulated by methylation (Figure 1(b)), leading tumors; however, despite numerous studies, the role of this to spliced mRNAs which results in CD133 isoforms with surface antigen in tumorigenesis and tumor progression is possibly distinct roles [2]. largely unknown [12]. In particular, it is not clear, and in part CD133 was firstly revealed as the target of a monoclonal controversial, the role of CD133 in breast tumors, the most antibody directed against the AC133 epitope expressed by a common malignancy and the second cause of cancer-related subpopulation of CD34 hematopoietic stem cells from the death among women in industrialized countries. )e aim of human fetal liver and bone marrow [3]. Despite the initial this review is to summarize the latest findings about the correlation of CD133 expression with progenitor cells [4, 5], meaning of CD133 in breast cancer, focusing on its re- accumulating evidence demonstrated that this surface lationship with the malignant evolution of the neoplasia. 2 Journal of Oncology EX EX NH TM TM TM TM TM IN Y828 IN Y852 COOH Src, Fyn Glycosylation site IN Intracellular cysteine-rich domain EX Extracellular domain Region modified by splicing TM Transmembrane domain Tyrosine phosphorylation consensus site (a) Notch1 HIF-1 p53 α SOX2 OCT4 P5 P1 P2 PROM1 P3 P4 RBP-Jk CpG islands (b) Figure 1: Structure and regulation of CD133. (a) CD133 protein structure in which the C-terminal tyrosine-phosphorylation consensus site, which comprises 5 tyrosine residues including Y828 and Y852, and the splice variants regions are indicated. (b) Schematic representation of the 5′ untranslated region of the CD133 gene. Transcription factors that positively (green circles) or negatively (red circles) regulate CD133 expression by direct binding to the different promoters are reported. )e direct binding of Notch1 to the site for RBP-Jk located upstream P1–P5 promoters is also indicated. to functional assays, these subpopulations showed increased 2. CD133 as a Cancer Stem Cell Marker growth, colony formation ability, migration, invasion, and Most of the studies in solid tumors have been focused on its induced tumorigenesis and metastasis in mice. In particular, high + + use as a surface marker for the detection of cells with stem- ALDH CD44 CD133 cells isolated from MDA-MB-231 like properties (i.e., cancer stem cells (CSCs)) [2, 13]. Due to and MDA-MB-468cell lines, displaying a triple negative its more restricted expression compared with other CSC phenotype (ER-, PR-, and HER2-), showed enhanced ma- markers such as CD44 and aldehyde dehydrogenase lignant/metastatic behavior both in vitro and in vivo [16]. + high (ALDH), CD133 has long been considered the most rigorous Furthermore, a subpopulation of CD44 CD49 CD133/ high indicator of malignant precursors in different solid tumors, 2 cells isolated from ER-negative tumors was demon- including breast cancer [14]. strated to be enriched for xenograft-initiating cells capable of In breast tumors, the role of CD133 as a CSC marker was giving rise to triple negative and ER-negative/HER2-positive firstly demonstrated in cell lines derived from BRCA1-as- tumors [17], endorsing CD133 as a suitable molecule for the sociated murine mammary tumors, in which CD133 cells identification of CSCs in the most aggressive subtypes of were shown to have a greater colony-forming efficiency, breast cancer. Indeed, when the expression of CD133 was higher proliferative rate, and greater capability to form evaluated in breast tumor cell lines with different pheno- tumors in NOD/SCID mice [15]. In human invasive breast types, a strong variability was found. In fact, the number of cancer cell lines, Croker et al. [16] firstly identified sub- CD133 cells ranged between 1 and 10% in claudin-low cells, populations of cells expressing CD133 together with the reached 80% in basal-like cell lines, and were between 1 and putative CSC markers CD44/CD24 and ALDH. When 2% in both luminal and HER2 cells, questioning the isolated by fluorescence-activated cell sorting and subjected equivalence between CD133 levels and stem-like properties Journal of Oncology 3 the subtypes of breast cancer [24]. More recently, the in breast tumor cells [18]. For this reason, although also recently it was used as the sole marker of CSCs [19], CD133 overexpression of both CD133 mRNA and protein were investigated in large well-characterized BC cohorts, resulting belongs to a well-known panel of molecules that, when properly combined, can actually identify cells with a stem- particularly high in TNBC and HER2 tumors and con- like phenotype in breast cancer cell lines and primary tumors firming the negative prognostic value of CD133 in all breast with different phenotypes [13, 20]. tumor subtypes [26]. In breast cancer, CD133 is also useful in predicting chemosensitivity to neoadjuvant chemotherapy (NAC) [32]. 3. CD133 as a Prognostic Marker Interestingly, the treatment with NAC resulted in the en- Although the data concerning the use of the only CD133 to richment of CD133 cells and in the positive correlation of identify CSCs are contradictory, the majority of the studies the surface antigen with prognosis, contrarily to its negative so far report for CD133 a significant predictive value [21]. significance in pre-NAC tumors [32]. )e potential role of Anyway, since CSCs generally express CD133, the prog- CD133 as a marker of chemoresistance in nonluminal breast nostic significance of this surface antigen is generally cor- cancer subtypes was also proposed, on the basis of the related with the stem-like properties of CD133 cells [13]. relative enrichment of CSCs expressing the surface antigen after systemic therapy [29]. )e role for CD133 as a prognostic marker in breast cancer was firstly demonstrated by Liu et al., who revealed that high PROM1 expression in invasive ductal carcinoma 3.1. CD133 Regulates Invasive Potential of TNBC-Derived positively correlates with adverse clinic-pathological factors, as tumor size and lymph node metastasis [22]. More re- Cells. Various signaling pathways, all directly involved in the acquisition of malignant properties, have been correlated cently, it was demonstrated that both CD133 mRNA and protein expression are important biomarkers for prognosis with CD133 levels in solid tumors, supporting its role in different stages of cancer development, including initiation, as they positively correlate with higher tumor grade, oc- currence of lymph node metastasis, negative PR and ER and progression, and metastasis [12]. )e identification of CD133 as a substrate for Src and Fyn families of tyrosine positive HER2 status, advanced TNM stage, and poor overall survival (OS) [23–25]. While both cytoplasmic and mem- kinases suggests that its cytoplasmic domain could play an brane CD133 were linked to shorter survival, membrane important role in the regulation of its functions (Figure 1(a)). In particular, the phosphorylation of tyrosine- positivity only seems to confer the worst patient outcome. Furthermore, high membrane expression of CD133 was 828 and tyrosine-852 may regulate interaction of CD133 with SH2-domain containing proteins, which may be in- significantly associated with younger age at diagnosis and premenopausal status [26]. volved in a number of intracellular signaling events [33], including the activation of PI3K/Akt pathway [34–37]. Despite the general relationship between CD133 and breast tumor malignancy, some controversies concern the At variance with other solid tumors, little is known about the signaling associated to CD133 in breast cancer cells significance of CD133 in tumors with a triple negative phenotype (TNBC), in which CD133 is strongly hypo- (Figure 2). Interestingly, the almost totality of the data on breast tumors correlate CD133 with molecules involved in methylated with respect to other breast cancer subtypes cell motility and invasion, suggesting a direct role of PROM1 [27]. A strong negative correlation of CD133 levels with clinical stage of TNBC tumors was firstly observed by Zhao in modulating the potential malignancy of breast tumors. A role of CD133 in regulating the migration rate of breast et al. [28], and the use of CD133 to detect circulating tumor cells in TNBC patients ratified its role in prognosis of this cancer cells was firstly revealed in a murine model and involved c-Met and STAT3, both downstream to the Wnt breast cancer subtype [29]. Still in TNBC, Cantile et al. suggested that poor prognosis is possibly due to a nuclear signaling and responsible of cancer invasion and metastasis [38]. A peculiar role of CD133 in the direct modulation of mislocalization of CD133, which normally shows a membrane, and more sporadically cytoplasmic, localiza- motility and invasive potential of breast tumor cells was demonstrated in the TNBC-derived MDA-MB-231cell line tion [30]. In contrast to all the previous experimental evidences, Collina et al., who described a prevalent cyto- that comprises a small cellular subset expressing high levels of CD133 at both membrane and cytoplasm levels. Re- plasmic expression of CD133, failed to reveal statistical markably, the CD133 high cells showed lower proliferation association of CD133 expression with TNBCs patients’ survival [31]. )is discordance may be at least in part [39], in accordance with the evidence of Di Bonito et al., indicating that only in TNBC, both CD133 mRNA and ascribed to the well-known problem that concerns the different antibodies used to detect CD133 by cytofluori- protein positively correlate with geminin, an inhibitor of cell cycle progression [40]. CD133 high cells also showed a larger metrical and immunohistochemical investigations [21], as well as to the absence of standardized criteria to define the adhesion area, consistent with a more differentiated phe- notype [39], according to the described role of CD133 in scores used for the quantification of the glycoprotein at membrane, cytoplasm, and nuclear level. regulating differentiation of normal mammary gland [10]. On the other hand, CD133 high cells exhibited greater in- A recent study performed with the Gene Expression- Based Outcome for Breast Cancer Online (GOBO) algo- vasion capability, suggestive of higher metastatic potential, in accordance with the positive correlation between CD133 rithm confirmed that CD133 mRNA is associated with and poor prognosis in breast cancer. At variance with other distant metastasis-free survival (DMFS) in patients with all 4 Journal of Oncology 4. CD133 as a Marker of Malignant Progression Hypoxia Induced by Low Oxygen Availability ATRA A crucial driving force in the progression towards a more aggressive and resistant tumor phenotype is the adaptation IL-6 PLC-β2 Notch1 of neoplastic cells to a state of reduced oxygen availability defined as hypoxia [47–52]. At least half of all solid tumors, HIF-1α including breast cancer, enclose hypoxic regions varying in Hur-MALAT1 amount and size, and recurring tumors often exhibit a hypoxic fraction higher than primary tumors [53]. Intra- CD133 tumoral hypoxia has been identified as an adverse prognostic Twist1 indicator independent of all the histopathological parame- Chemoresistance ters and, in breast cancer, as in many other solid cancers, low Geminin Vasculogenic mimicry Tm4 AdoHcyase oxygen availability has been reported as associated with a Wnt signaling clinically aggressive tumor behavior [54]. Autophagy (c-Met, STAT3) In solid tumors, including breast cancer, CD133 is EMT generally induced by low oxygen availability via upregula- cell motility Proliferation tion HIF-1α (Figures 1(b) and 2), even though only in colon invasion differentiation cancer cells a physical interaction of HIF-1α with the CD133 apoptosis promoter was demonstrated [55–58]. Once again, the almost Figure 2: Regulation and functional roles of CD133 in breast totality of the studies correlating CD133 with low oxygen cancer. Schematic summary of the main mechanisms regulating availability looked at PROM1 as a marker of CSCs, known to CD133 gene expression in breast cancer cells (green circles: positive increase under hypoxia [50]. regulators; red circles: negative regulators) and of cellular events In breast tumors, Currie et al. firstly associated the ex- directly targeted by CD133 and involved in breast cancer pression of CD133 with markers of hypoxia and/or tumor progression. microvasculature in invasive and noninvasive breast carci- noma [23] although most of the further studies correlating CD133 to low oxygen availability were performed in TNBC. studies, these data highlight the value of both the number of In MDA-MB-231-derived xenografts, CD133 cells with CD133 cells and the expression levels of the surface antigen, cancer stem cell characteristics were related to vasculogenic which at least in part may justify some discrepancies on the mimicry (VM) (Figure 2) and hypoxia induced by the described prognostic role of CD133 in breast tumors. antiangiogenic agent sunitinib [59]. In the same cell model, When MDA-MB-231 subpopulations expressing dif- only CD133 cells formed VM channels in Matrigel after ferent levels of CD133 were subjected to two-dimensional reoxygenation, suggesting that hypoxia accelerates VM by electrophoresis followed by mass spectrometry, specific stimulating the CSC population [60]. Again in TNBCs, protein signatures were found, including proteins known to chemoresistance was associated with higher numbers of be deregulated and to play crucial roles in breast cancer [39]. CD133/ALDH1 or CD133/CD146 coexpressing cells that As expected, the fastest CD133 low cells expressed lower were in a quiescent autophagic state related to hypoxia [61]. levels of proteins involved in cell cycle and apoptosis, and the A further correlation of CD133 with autophagy induced by most invasive CD133 high cells showed higher expression of low oxygen availability was performed in patient-derived proteins with an oncogenic/metastatic role. )e CD133- TNBC xenografts, in which hypoxia increased drug re- related proteins included the actin-binding protein tropo- sistance of CD133 cells, and the inhibition of the auto- myosin4 (Tm4), upregulated in highly metastatic breast phagic pathway reversed chemoresistance [61]. cancer cell lines and associated with lymph node metastasis More recent in vitro studies suggest that the effects of of breast tumors [41] and AdoHcyase (Figure 2), known to hypoxia on the expression of CD133 in breast tumor cells are play a key role in the control of DNA methylation [42] and in closely related to their phenotype, and particularly to their the regulation of cell cycle, apoptosis, and cellular differ- ER status. In fact, low oxygen availability seems to induce entiation of breast tumor cells [43]. Of note, the silencing of CD133 only in ER cells and mostly in cells belonging to the CD133 in CD133 high cells reduced invasiveness and ex- luminal A subtype [62]. At variance with experiments in pression of Tm4, ascertaining the existence of direct which hypoxia was pharmacologically induced in xenografts mechanisms by which CD133 can promote invasiveness of [60], no significant modifications of CD133 were revealed in TNBC-derived cells [39]. TNBC-derived cells cultured under low oxygen [62]. At the A relationship between CD133 and EMT markers was basis of this discrepancy could be the change of the gly- demonstrated in tumors cells from metastatic breast cancer cosylation status of CD133 induced by hypoxia, in turn patients. In particular, the concomitant overexpression of responsible of abnormal detection of the extracellular gly- N-cadherin and CD133 was revealed in both circulating cosylated AC133 epitope, as observed in glioma cells [63]. tumor cells [44, 45] and breast cancer specimens [46], even if Since hypoxia improves both the number of cells a significant correlation between the two molecules and expressing high levels of CD133 and the malignant potential patient’s prognosis was not fully demonstrated. Journal of Oncology 5 of the noninvasive MCF10DCIS cells [64], the increase of MDA-MB-231cells, in which overexpression of the PLC CD133 was considered a marker of malignant evolution significantly reduced both membrane-associated and cyto- plasmic levels of CD133, in parallel with the CD133-related induced by low oxygen availability in both noninvasive and low-invasive breast tumors. invasion capability [46]. In the same cell model, PLC-β2 regulates the amount of CD133 cells with stem-like fea- tures. In particular, overexpression of PLC-β2 reduced the 5. Regulation of CD133 Levels + + + number of CD44 /CD133 /EpCAM cells and proliferation + + and invasion capability of the CD133 /EpCAM cellular )e expression of CD133 is controlled by many extracellular subset [74]. and intracellular agents, and hypoxic tumor microenvi- A role of PLC-β2 in modulating CD133 expression was ronment and mitochondria dysfunctions seem to be the also demonstrated in breast tumor derived cells under main events modulating CD133 levels [2, 11]. In particular, hypoxia. In particular, culture at low oxygen availability hypoxia can improve the levels of the CD133 mRNA by reduced PLC-β2 amount and increased CD133 expression in acting at transcriptional level and can increase the recovery ER breast tumor cells. Counteracting the decrease of PLC- of the AC133 epitope, by regulating its glycosylation status β2 prevented the increase of CD133 induced by hypoxia and [58, 63]. significantly reduced the hypoxia-related accumulation of Apart from the hypoxia-related role of HIF-1α, there is a HIF-1α (Figure 2), a putative regulator of CD133 in this cell general agreement that the transcription factors that interact model [62]. )e same study demonstrated that PLC-β2 is not with CD133 promoters are tumor dependent [12]. For this modified by hypoxia in TNBC-derived cells, in which low reason, although substantial evidence assigns to the increase oxygen availability fails to induce CD133. On the other hand, of CD133 levels a crucial role in the malignant potential of its forced expression induced a decrease of the number of various solid tumors, the regulatory mechanisms that pro- CD133 cells, confirming, also in this breast tumor subtype, mote CD133 expression are still largely unknown in breast the role of PLC-β2 in downregulating CD133 [62]. cancer. )e relationship between CD133 cancer stem cells PLC-β2 is ectopically expressed and regulates the and the Notch signaling was shown in several tumors, in- number of cells expressing CD133 also in the noninvasive cluding breast cancer [65, 66], but only in gastric cancer MCF10DCIS cells [75]. In the same cell model, the ad- cells, the direct binding of Notch 1 with the promoter region ministration of all trans retinoic acid (ATRA), currently of CD133 was demonstrated [67]. In colon cancer and os- used in the management of acute promyelocytic leukemia teosarcoma, CD133 expression is negatively regulated by [76] in which it induces the expression of PLC-β2 [77], direct binding of p53 to a noncanonical p53-binding se- counteracts the effects of hypoxia on CD133 expression by quence in the CD133 promoter [68]. Moreover, TGFβ1 is up-modulating the PLC isozyme [64]. )ese data constitute able to regulate CD133 expression in hepatocellular carci- the first evidence that CD133 levels can be modulated by noma through inhibition of DNMT1 and DNMT3β ex- acting on specific signaling molecules and suggest that ag- pression [69] (Figure 1(b)). onists able to upmodulate PLC-β2 could counteract the Abnormal DNA methylation, usually reported in many CD133-related malignant properties in noninvasive and human cancers, seems to play a critical role in CD133 ex- invasive breast tumor cells. pression, and deregulation of the methylation status was proposed to be at the basis of increased CD133 expression in breast cancer. In particular, D’Anello and colleagues [70] 6. Conclusion reported that IL-6 induced loss of methylation at CD133 promoter enhancing CD133 gene transcription in basal-like )is review collects the data concerning the expression of breast cancer via an autocrine loop triggered by the in- CD133 in breast cancer in which this surface antigen is activation of p53. Moreover, in cells with a luminal A generally associated with a stem cell-like phenotype. In phenotype, but not in TNBC-derived cells, the expression of parallel with the role as a cancer stem cell marker, we CD133 was linked to MALAT1, one of the most widely reviewed the value of CD133 as a prognostic factor and studied long coding RNA in cancer development and indicator of malignant progression of breast tumors, progression, and to the RNA binding protein HuR highlighting its direct role in modulating invasive potential (Figure 1(b)). HuR/MALAT1 impact on CD133 gene ex- of breast tumor cells with a triple negative phenotype. We pression can regulate EMT features, suggesting that the also revised the mechanisms regulating CD133 gene ex- specific regulation of these molecules could control, at least pression in both noninvasive and invasive breast tumor cells, in part, the CD133-related tumor progression [71]. underlining experimental strategies capable to limit its ex- pression level that could constitute the basis for new ther- apeutic approaches to reduce malignancy and/or to prevent 5.1. PLC-β2 Regulates CD133 in Breast Cancer Cells. An progression of breast tumors. unexpected role in the regulation of CD133 mRNA in breast tumor cells was reported for the beta-2 isoform of PLC (PLC-β2) (Figure 2), poorly expressed in normal breast Conflicts of Interest tissues and upregulated in tumor cells, in which sustains motility of invasive cells [72, 73]. )e first evidence of a )e authors declare that there are no conflicts of interest direct regulation of CD133 by PLC-β2 was obtained in regarding the publication of this paper. 6 Journal of Oncology [15] M. H. Wright, A. M. Calcagno, C. D. Salcido, M. D. Carlson, Authors’ Contributions S. V. Ambudkar, and L. Varticovski, “Brca1 breast tumors + – + contain distinct CD44 /CD24 and CD133 cells with cancer Federica Brugnoli and Silvia Grassilli contributed equally to stem cell characteristics,” Breast Cancer Research, vol. 10, this article. no. 1, p. R10, 2008. [16] A. K. Croker, D. Goodale, J. Chu et al., “High aldehyde de- Acknowledgments hydrogenase and expression of cancer stem cell markers se- lects for breast cancer cells with enhanced malignant and )is work was supported by grants from the University of metastatic ability,” Journal of Cellular and Molecular Medi- Ferrara (Italy) to VB and SC and from Unife-CCIAA cine, vol. 13, no. 8b, pp. 2236–2252, 2009. (Ferrara, Italy) to VB. [17] M. J. Meyer, J. M. Fleming, A. F. Lin, S. A. Hussnain, pos hi E. Ginsburg, and B. K. Vonderhaar, “CD44 CD49f CD133/ References hi 2 defines xenograft-initiating cells in estrogen receptor- negative breast cancer,” Cancer Research, vol. 70, no. 11, [1] D. Corbeil, K. Roper, C. A. Fargeas, A. Joester, and pp. 4624–4633, 2010. W. B. Huttner, “Prominin: a story of cholesterol, plasma [18] S. Borgna, M. Armellin, A. di Gennaro, R. Maestro, and membrane protrusions and human pathology,” Traffic, vol. 2, M. Santarosa, “Mesenchymal traits are selected along with no. 2, pp. 82–91, 2001. stem features in breast cancer cells grown as mammospheres,” [2] P. M. Glumac and A. M. LeBeau, “)e role of CD133 in Cell Cycle, vol. 11, no. 22, pp. 4242–4251, 2012. cancer: a concise review,” Clinical and Translational Medicine, [19] W. Zheng, B. Duan, Q. Zhang et al., “Vitamin D-induced vol. 7, no. 1, p. 18, 2018. vitamin D receptor expression induces tamoxifen sensitivity [3] A. H. Yin, S. Miraglia, E. D. Zanjani et al., “AC133, a novel in MCF-7 stem cells via suppression of Wnt/β-catenin sig- marker for human hematopoietic stem and progenitor cells,” naling,” Bioscience Reports, vol. 38, no. 6, Article ID Blood, vol. 90, no. 12, pp. 5002–5012, 1997. BSR20180595, 2018. [4] P. Salven, S. Mustjoki, R. Alitalo, K. Alitalo, and S. Rafii, [20] R. V. Oliveira, V. B. Souza, P. C. Souza et al., “Detection of “VEGFR-3 and CD133 identify a population of CD34+ putative stem-cell markers in invasive ductal carcinoma of the lymphatic/vascular endothelial precursor cells,” Blood, breast by immunohistochemistry: does it improve prognostic/ vol. 101, no. 1, pp. 168–172, 2003. predictive assessments?,” Applied Immunohistochemistry & [5] C. A. Fargeas, A.-V. Fonseca, W. B. Huttner, and D. Corbeil, Molecular Morphology, vol. 26, no. 10, pp. 760–768, 2018. “Prominin-1 (CD133): from progenitor cells to human dis- [21] P. Grosse-Gehling, C. A. Fargeas, C. Dittfeld et al., “CD133 as eases,” Future Lipidology, vol. 1, no. 2, pp. 213–225, 2006. a biomarker for putative cancer stem cells in solid tumours: [6] C. A. Fargeas, A. Joester, E. Missol-Kolka, A. Hellwig, limitations, problems and challenges,” 2e Journal of Pa- W. B. Huttner, and D. Corbeil, “Identification of novel thology, vol. 229, no. 3, pp. 355–378, 2013. Prominin-1/CD133 splice variants with alternative C-termini [22] Q. Liu, J. G. Li, X. Y. Zheng, F. Jin, and H. T. Dong, “Ex- and their expression in epididymis and testis,” Journal of Cell pression of CD133, PAX2, ESA, and GPR30 in invasive ductal Science, vol. 117, no. 18, pp. 4301–4311, 2004. breast carcinomas,” Chinese Medical Journal, vol. 122, no. 22, [7] G. D. Richardson, C. N. Robson, S. H. Lang, D. E. Neal, pp. 2763–2769, 2009. N. J. Maitland, and A. T. Collins, “CD133, a novel marker for [23] M. J. Currie, B. E. Beardsley, G. C. Harris et al., “Immuno- human prostatic epithelial stem cells,” Journal of Cell Science, histochemical analysis of cancer stem cell markers in invasive vol. 117, no. 16, pp. 3539–3545, 2004. breast carcinoma and associated ductal carcinoma in situ: [8] M. Florek, M. Haase, A.-M. Marzesco et al., “Prominin-1/ relationships with markers of tumor hypoxia and micro- CD133, a neural and hematopoietic stem cell marker, is vascularity,” Human Pathology, vol. 44, no. 3, pp. 402–411, expressed in adult human differentiated cells and certain types of kidney cancer,” Cell and Tissue Research, vol. 319, no. 1, [24] P. Xia, “CD133 mRNA may be a suitable prognostic marker pp. 15–26, 2005. for human breast cancer,” Stem Cell Investigation, vol. 4, [9] H. T. Hassan, X. Zhai, and J. A. Goodacre, “CD133 stem cells no. 11, p. 87, 2017. in adult human brain,” Journal of Neuro-Oncology, vol. 89, [25] L. Han, X. Gao, X. Gu et al., “Prognostic significance of cancer no. 2, pp. 247-248, 2008. stem cell marker CD133 expression in breast cancer,” In- [10] L. H. Anderson, C. A. Boulanger, G. H. Smith, P. Carmeliet, ternational Journal of Clinical and Experimental Medicine, and C. J. Watson, “Stem cell marker prominin-1 regulates vol. 10, no. 3, pp. 4829–4837, 2017. branching morphogenesis, but not regenerative capacity, in [26] C. Joseph, M. Arshad, S. Kurozomi et al., “Overexpression of the mammary gland,” Developmental Dynamics, vol. 240, the cancer stem cell marker CD133 confers a poor prognosis no. 3, pp. 674–681, 2011. in invasive breast cancer,” Breast Cancer Research and [11] A. Barzegar Behrooz, A. Syahir, and S. Ahmad, “CD133: Treatment, vol. 174, no. 2, pp. 387–399, 2019. beyond a cancer stem cell biomarker,” Journal of Drug Tar- [27] N. Kagara, K. T. Huynh, C. Kuo et al., “Epigenetic regulation geting, vol. 17, pp. 1–13, 2018. [12] G. Y. Liou, “CD133 as a regulator of cancer metastasis through of cancer stem cell genes in triple-negative breast cancer,” 2e American Journal of Pathology, vol. 181, no. 1, pp. 257–267, the cancer stem cells,” 2e International Journal of Bio- chemistry & Cell Biology, vol. 106, pp. 1–7, 2019. 2012. [28] P. Zhao, Y. Lu, X. Jiang, and X. Li, “Clinicopathological [13] M. Najafi, B. Farhood, and K. Mortezaee, “Cancer stem cells (CSCs) in cancer progression and therapy,” Journal of Cellular significance and prognostic value of CD133 expression in triple-negative breast carcinoma,” Cancer Science, vol. 102, Physiology, vol. 234, no. 6, pp. 8381–8395, 2019. [14] A. Lorico and G. Rappa, “Phenotypic heterogeneity of breast no. 5, pp. 1107–1111, 2011. [29] R. Nadal, F. G. Ortega, M. Salido et al., “CD133 expression in cancer stem cells,” Journal of Oncology, vol. 2011, Article ID 135039, 6 pages, 2011. circulating tumor cells from breast cancer patients: potential Journal of Oncology 7 role in resistance to chemotherapy,” International Journal of tumor cells of metastatic breast cancer patients,” Breast Cancer, vol. 133, no. 10, pp. 2398–2407, 2013. Cancer Research, vol. 11, no. 4, p. R46, 2009. [30] M. Cantile, F. Collina, M. D’Aiuto et al., “Nuclear localization [45] A. J. Armstrong, M. S. Marengo, S. Oltean et al., “Circulating of cancer stem cell marker CD133 in triple-negative breast tumor cells from patients with advanced prostate and breast cancer: a case report,” Tumori Journal, vol. 99, no. 5, cancer display both epithelial and mesenchymal markers,” pp. e245–e250, 2013. Molecular Cancer Research, vol. 9, no. 8, pp. 997–1007, 2011. [31] F. Collina, M. Di Bonito, V. Li Bergolis et al., “Prognostic [46] C. Bock, C. Kuhn, N. Ditsch et al., “Strong correlation be- value of cancer stem cells markers in triple-negative breast tween N-cadherin and CD133 in breast cancer: role of both cancer,” BioMed Research International, vol. 2015, Article ID markers in metastatic events,” Journal of Cancer Research and 158682, 10 pages, 2015. Clinical Oncology, vol. 140, no. 11, pp. 1873–1881, 2014. [32] N. Aomatsu, M. Yashiro, S. Kashiwagi et al., “CD133 is a [47] L. Schito and G. L. Semenza, “Hypoxia-Inducible factors: useful surrogate marker for predicting chemosensitivity to master regulators of cancer progression,” Trends in Cancer, neoadjuvant chemotherapy in breast cancer,” PLoS One, vol. 2, no. 12, pp. 758–770, 2016. vol. 7, no. 9, Article ID e45865, 2012. [48] K. R. Luoto, R. Kumareswaran, and R. G. Bristow, “Tumor [33] D. Boivin, D. Labbé, N. Fontaine et al., “)e stem cell marker hypoxia as a driving force in genetic instability,” Genome CD133 (Prominin-1) is phosphorylated on cytoplasmic ty- Integrity, vol. 4, no. 1, p. 5, 2013. rosine-828 and tyrosine-852 by Src and Fyn tyrosine kinases,” [49] S. Chouaib, M. Z. Noman, K. Kosmatopoulos, and Biochemistry, vol. 48, no. 18, pp. 3998–4007, 2009. M. A. Curran, “Hypoxic stress: obstacles and opportunities for [34] A. Dubrovska, S. Kim, R. J. Salamone et al., “)e role of innovative immunotherapy of cancer,” Oncogene, vol. 36, PTEN/Akt/PI3K signaling in the maintenance and viability of no. 4, pp. 439–445, 2017. prostate cancer stem-like cell populations,” Proceedings of the [50] A. Mohyeldin, T. Garzon-Muvdi, and A. Quiñones-Hinojosa, National Academy of Sciences, vol. 106, no. 1, pp. 268–273, “Oxygen in stem cell biology: a critical component of the stem cell niche,” Cell Stem Cell, vol. 7, no. 2, pp. 150–161, 2010. [35] H. Sartelet, T. Imbriglio, C. Nyalendo et al., “CD133 ex- [51] E. B. Rankin, J.-M. Nam, and A. J. Giaccia, “Hypoxia: sig- pression is associated with poor outcome in neuroblastoma naling the metastatic cascade,” Trends in Cancer, vol. 2, no. 6, via chemoresistance mediated by the AKT pathway,” Histo- pp. 295–304, 2016. pathology, vol. 60, no. 7, pp. 1144–1155, 2012. [52] S. Marx, M. Van Gysel, A. Breuer et al., “Potentialization of [36] Y. Wei, Y. Jiang, F. Zou et al., “Activation of PI3K/Akt anticancer agents by identification of new chemosensitizers pathway by CD133-p85 interaction promotes tumorigenic active under hypoxia,” Biochem Pharmacol, vol. 162, capacity of glioma stem cells,” Proceedings of the National pp. 224–236, 2019. Academy of Sciences, vol. 110, no. 17, pp. 6829–6834, 2013. [53] V. Bhandari, C. Hoey, L. Y. Liu et al., “Molecular landmarks of [37] J. U. Schmohl and D. A. Vallera, “CD133, selectively targeting tumor hypoxia across cancer types,” Nature Genetics, vol. 51, the root of cancer,” Toxins, vol. 8, 2016. no. 2, pp. 308–318, 2019. [38] J. Sun, C. Zhang, G. Liu et al., “A novel mouse CD133 [54] J. C. Walsh, A. Lebedev, E. Aten, K. Madsen, L. Marciano, and binding-peptide screened by phage display inhibits cancer cell H. C. Kolb, “)e clinical importance of assessing tumor motility in vitro,” Clinical & Experimental Metastasis, vol. 29, hypoxia: relationship of tumor hypoxia to prognosis and no. 3, pp. 185–196, 2012. therapeutic opportunities,” Antioxidants & Redox Signaling, [39] F. Brugnoli, S. Grassilli, M. Piazzi et al., “In triple negative vol. 21, no. 10, pp. 1516–1554, 2014. breast tumor cells, PLC-β2 promotes the conversion of high low [55] A. Soeda, M. Park, D. Lee et al., “Hypoxia promotes expansion CD133 to CD133 phenotype and reduces the CD133- of the CD133-positive glioma stem cells through activation of related invasiveness,” Molecular Cancer, vol. 12, no. 1, p. 165, HIF-1α,” Oncogene, vol. 28, no. 45, pp. 3949–3959, 2009. [56] L. P. Schwab, D. L. Peacock, D. Majumdar et al., “Hypoxia- [40] M. Di Bonito, M. Cantile, F. Collina et al., “Overexpression of inducible factor 1α promotes primary tumor growth and cell cycle progression inhibitor geminin is associated with tumor-initiating cell activity in breast cancer,” Breast Cancer tumor stem-like phenotype of triple-negative breast cancer,” Research, vol. 14, no. 1, p. R6, 2012. Journal of Breast Cancer, vol. 15, no. 2, pp. 162–171, 2012. [57] K. Maeda, Q. Ding, M. Yoshimitsu et al., “CD133 modulate [41] H. Li, F. Li, Z. M. Qian, and H. Sun, “Structure and topology of HIF-1alpha expression under hypoxia in emt phenotype the transmembrane domain 4 of the divalent metal trans- pancreatic cancer stem-like cells,” International Journal of porter in membrane-mimetic environments,” European Molecular Sciences, vol. 17, no. 7, Article ID E1025, 2016. Journal of Biochemistry, vol. 271, no. 10, pp. 1938–1951, 2004. [58] S. Ohnishi, O. Maehara, K. Nakagawa et al., “hypoxia-in- [42] H. Gellekink, M. d. Heijer, L. A. J. Kluijtmans, and H. J. Blom, ducible factors activate CD133 promoter through ETS family “Effect of genetic variation in the human S-adenosylhomo- transcription factors,” PLoS One, vol. 8, no. 6, Article ID cysteine hydrolase gene on total homocysteine concentrations e66255, 2013. and risk of recurrent venous thrombosis,” European Journal of [59] T. J. Liu, B. C. Sun, X. L. Zhao et al., “CD133 cells with cancer Human Genetics, vol. 12, no. 11, pp. 942–948, 2004. stem cell characteristics associates with vasculogenic mimicry [43] A. Hayden, P. W. M. Johnson, G. Packham, and S. J. Crabb, in triple-negative breast cancer,” Oncogene, vol. 32, no. 5, “S-adenosylhomocysteine hydrolase inhibition by 3-deaza- pp. 544–553, 2013. neplanocin A analogues induces anti-cancer effects in breast [60] D. Zhang, B. Sun, X. Zhao et al., “Twist1 expression induced cancer cell lines and synergy with both histone deacetylase by sunitinib accelerates tumor cell vasculogenic mimicry by and HER2 inhibition,” Breast Cancer Research and Treatment, vol. 127, no. 1, pp. 109–119, 2011. increasing the population of CD133 cells in triple-negative [44] B. Aktas, M. Tewes, T. Fehm, S. Hauch, R. Kimmig, and breast cancer,” Molecular Cancer, vol. 13, no. 1, p. 207, 2014. [61] G. Bousquet, M. El Bouchtaoui, T. Sophie et al., “Targeting S. Kasimir-Bauer, “Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating autophagic cancer stem-cells to reverse chemoresistance in 8 Journal of Oncology human triple negative breast cancer,” Oncotarget, vol. 8, [77] V. Bertagnolo, M. Marchisio, S. Pierpaoli et al., “Selective up- no. 21, pp. 35205–35221, 2017. regulation of phospholipase C-β2 during granulocytic dif- [62] F. Brugnoli, S. Grassilli, Y. Al-Qassab, S. Capitani, and ferentiation of normal and leukemic hematopoietic pro- V. Bertagnolo, “PLC-β2 is modulated by low oxygen avail- genitors,” Journal of Leukocyte Biology, vol. 71, pp. 957–965, ability in breast tumor cells and plays a phenotype dependent role in their hypoxia-related malignant potential,” Molecular Carcinogenesis, vol. 55, no. 12, pp. 2210–2221, 2016. [63] K. S. Lehnus, L. K. Donovan, X. Huang et al., “CD133 gly- cosylation is enhanced by hypoxia in cultured glioma stem cells,” International Journal of Oncology, vol. 42, no. 3, pp. 1011–1017, 2013. [64] Y. Al-Qassab, S. Grassilli, F. Brugnoli, F. Vezzali, S. Capitani, and V. Bertagnolo, “Protective role of all-trans retinoic acid (ATRA) against hypoxia-induced malignant potential of non- invasive breast tumor derived cells,” BMC Cancer, vol. 18, no. 1, p. 1194, 2018. [65] P. Sansone, M. Berishaj, V. K. Rajasekhar et al., “Evolution of cancer stem-like cells in endocrine-resistant metastatic breast cancers is mediated by stromal microvesicles,” Cancer Re- search, vol. 77, no. 8, pp. 1927–1941, 2017. [66] S. K. Saha, H. Y. Choi, B. W. Kim et al., “KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB- dependent NOTCH signaling pathway and breast cancer properties,” Oncogene, vol. 36, no. 3, pp. 332–349, 2017. [67] H. Konishi, N. Asano, A. Imatani et al., “Notch1 directly induced CD133 expression in human diffuse type gastric cancers,” Oncotarget, vol. 7, pp. 56598–56607, 2016. [68] E. K. Park, J. C. Lee, J. W. Park et al., “Transcriptional re- pression of cancer stem cell marker CD133 by tumor sup- pressor p53,” Cell Death & Disease, vol. 6, no. 11, Article ID e1964, 2015. [69] H. You, W. Ding, and C. B. Rountree, “Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-β,” Hepatology, vol. 51, no. 5, pp. 1635–1644, 2010. [70] L. D’Anello, P. Sansone, G. Storci et al., “Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells,” Molecular Cancer, vol. 9, no. 1, p. 300, [71] E. Latorre, S. Carelli, I. Raimondi et al., “)e ribonucleic complex hur-MALAT1 represses CD133 expression and suppresses epithelial-mesenchymal transition in breast can- cer,” Cancer Research, vol. 76, no. 9, pp. 2626–2636, 2016. [72] V. Bertagnolo, M. Benedusi, P. Querzoli et al., “PLC-beta2 is highly expressed in breast cancer and is associated with a poor outcome: a study tissue microarrays,” International Journal of Oncology, vol. 28, no. 4, pp. 863–872, 2006. [73] V. Bertagnolo, M. Benedusi, F. Brugnoli et al., “Phospholipase C-β2 promotes mitosis and migration of human breast cancer-derived cells,” Carcinogenesis, vol. 28, no. 8, pp. 1638–1645, 2007. [74] F. Brugnoli, S. Grassilli, P. Lanuti et al., “Up-modulation of PLC-β2 reduces the number and malignancy of triple-neg- + + ative breast tumor cells with a CD133 /EpCAM phenotype: a promising target for preventing progression of TNBC,” BMC Cancer, vol. 17, no. 1, p. 617, 2017. [75] V. Bertagnolo, S. Grassilli, S. Volinia et al., “Ectopic ex- pression of PLC-β2 in non-invasive breast tumor cells plays a protective role against malignant progression and is corre- lated with the deregulation of miR-146a,” Molecular Carci- nogenesis, vol. 58, no. 5, 2018. [76] S. Kayser, R. F. Schlenk, and U. Platzbecker, “Management of patients with acute promyelocytic leukemia,” Leukemia, vol. 32, no. 6, pp. 1277–1294, 2018. 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CD133 in Breast Cancer Cells: More than a Stem Cell Marker

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Copyright © 2019 Federica Brugnoli et al. 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.
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10.1155/2019/7512632
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Abstract

Hindawi Journal of Oncology Volume 2019, Article ID 7512632, 8 pages https://doi.org/10.1155/2019/7512632 Review Article 1 1 1,2 1 Federica Brugnoli, Silvia Grassilli, Yasamin Al-Qassab, Silvano Capitani, and Valeria Bertagnolo Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy College of Medicine, University of Baghdad, Baghdad, Iraq Correspondence should be addressed to Valeria Bertagnolo; bgv@unife.it Received 26 April 2019; Accepted 10 August 2019; Published 16 September 2019 Guest Editor: Chia-Jung Li Copyright © 2019 Federica Brugnoli et al. )is 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. Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in in- dustrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. )e molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors. antigen also characterizes adult tissues, including mammary 1. Introduction gland [6–10]. In normal breast tissue, CD133 is not a stem CD133/prominin 1 (PROM1) is a pentaspan trans- cell marker and plays a role in morphogenesis, regulating membrane single-chain glycoprotein (Figure 1(a)) mainly ductal branching and the ratio of luminal to basal cells [10]. localized into protrusions of cellular plasma membrane and Even though CD133 has been variously associated with particularly in the cholesterol-based lipid microdomains, proliferation, cell survival, and autophagy, in precursors indicative of its involvement in membrane organization [1]. and/or mature cells [11], its exact role is not well defined and Transcription of human CD133 is driven by five tissue- a specific ligand was not discovered. specific promoters, three of which located in CpG islands )e expression of CD133 is deregulated in various solid and partially regulated by methylation (Figure 1(b)), leading tumors; however, despite numerous studies, the role of this to spliced mRNAs which results in CD133 isoforms with surface antigen in tumorigenesis and tumor progression is possibly distinct roles [2]. largely unknown [12]. In particular, it is not clear, and in part CD133 was firstly revealed as the target of a monoclonal controversial, the role of CD133 in breast tumors, the most antibody directed against the AC133 epitope expressed by a common malignancy and the second cause of cancer-related subpopulation of CD34 hematopoietic stem cells from the death among women in industrialized countries. )e aim of human fetal liver and bone marrow [3]. Despite the initial this review is to summarize the latest findings about the correlation of CD133 expression with progenitor cells [4, 5], meaning of CD133 in breast cancer, focusing on its re- accumulating evidence demonstrated that this surface lationship with the malignant evolution of the neoplasia. 2 Journal of Oncology EX EX NH TM TM TM TM TM IN Y828 IN Y852 COOH Src, Fyn Glycosylation site IN Intracellular cysteine-rich domain EX Extracellular domain Region modified by splicing TM Transmembrane domain Tyrosine phosphorylation consensus site (a) Notch1 HIF-1 p53 α SOX2 OCT4 P5 P1 P2 PROM1 P3 P4 RBP-Jk CpG islands (b) Figure 1: Structure and regulation of CD133. (a) CD133 protein structure in which the C-terminal tyrosine-phosphorylation consensus site, which comprises 5 tyrosine residues including Y828 and Y852, and the splice variants regions are indicated. (b) Schematic representation of the 5′ untranslated region of the CD133 gene. Transcription factors that positively (green circles) or negatively (red circles) regulate CD133 expression by direct binding to the different promoters are reported. )e direct binding of Notch1 to the site for RBP-Jk located upstream P1–P5 promoters is also indicated. to functional assays, these subpopulations showed increased 2. CD133 as a Cancer Stem Cell Marker growth, colony formation ability, migration, invasion, and Most of the studies in solid tumors have been focused on its induced tumorigenesis and metastasis in mice. In particular, high + + use as a surface marker for the detection of cells with stem- ALDH CD44 CD133 cells isolated from MDA-MB-231 like properties (i.e., cancer stem cells (CSCs)) [2, 13]. Due to and MDA-MB-468cell lines, displaying a triple negative its more restricted expression compared with other CSC phenotype (ER-, PR-, and HER2-), showed enhanced ma- markers such as CD44 and aldehyde dehydrogenase lignant/metastatic behavior both in vitro and in vivo [16]. + high (ALDH), CD133 has long been considered the most rigorous Furthermore, a subpopulation of CD44 CD49 CD133/ high indicator of malignant precursors in different solid tumors, 2 cells isolated from ER-negative tumors was demon- including breast cancer [14]. strated to be enriched for xenograft-initiating cells capable of In breast tumors, the role of CD133 as a CSC marker was giving rise to triple negative and ER-negative/HER2-positive firstly demonstrated in cell lines derived from BRCA1-as- tumors [17], endorsing CD133 as a suitable molecule for the sociated murine mammary tumors, in which CD133 cells identification of CSCs in the most aggressive subtypes of were shown to have a greater colony-forming efficiency, breast cancer. Indeed, when the expression of CD133 was higher proliferative rate, and greater capability to form evaluated in breast tumor cell lines with different pheno- tumors in NOD/SCID mice [15]. In human invasive breast types, a strong variability was found. In fact, the number of cancer cell lines, Croker et al. [16] firstly identified sub- CD133 cells ranged between 1 and 10% in claudin-low cells, populations of cells expressing CD133 together with the reached 80% in basal-like cell lines, and were between 1 and putative CSC markers CD44/CD24 and ALDH. When 2% in both luminal and HER2 cells, questioning the isolated by fluorescence-activated cell sorting and subjected equivalence between CD133 levels and stem-like properties Journal of Oncology 3 the subtypes of breast cancer [24]. More recently, the in breast tumor cells [18]. For this reason, although also recently it was used as the sole marker of CSCs [19], CD133 overexpression of both CD133 mRNA and protein were investigated in large well-characterized BC cohorts, resulting belongs to a well-known panel of molecules that, when properly combined, can actually identify cells with a stem- particularly high in TNBC and HER2 tumors and con- like phenotype in breast cancer cell lines and primary tumors firming the negative prognostic value of CD133 in all breast with different phenotypes [13, 20]. tumor subtypes [26]. In breast cancer, CD133 is also useful in predicting chemosensitivity to neoadjuvant chemotherapy (NAC) [32]. 3. CD133 as a Prognostic Marker Interestingly, the treatment with NAC resulted in the en- Although the data concerning the use of the only CD133 to richment of CD133 cells and in the positive correlation of identify CSCs are contradictory, the majority of the studies the surface antigen with prognosis, contrarily to its negative so far report for CD133 a significant predictive value [21]. significance in pre-NAC tumors [32]. )e potential role of Anyway, since CSCs generally express CD133, the prog- CD133 as a marker of chemoresistance in nonluminal breast nostic significance of this surface antigen is generally cor- cancer subtypes was also proposed, on the basis of the related with the stem-like properties of CD133 cells [13]. relative enrichment of CSCs expressing the surface antigen after systemic therapy [29]. )e role for CD133 as a prognostic marker in breast cancer was firstly demonstrated by Liu et al., who revealed that high PROM1 expression in invasive ductal carcinoma 3.1. CD133 Regulates Invasive Potential of TNBC-Derived positively correlates with adverse clinic-pathological factors, as tumor size and lymph node metastasis [22]. More re- Cells. Various signaling pathways, all directly involved in the acquisition of malignant properties, have been correlated cently, it was demonstrated that both CD133 mRNA and protein expression are important biomarkers for prognosis with CD133 levels in solid tumors, supporting its role in different stages of cancer development, including initiation, as they positively correlate with higher tumor grade, oc- currence of lymph node metastasis, negative PR and ER and progression, and metastasis [12]. )e identification of CD133 as a substrate for Src and Fyn families of tyrosine positive HER2 status, advanced TNM stage, and poor overall survival (OS) [23–25]. While both cytoplasmic and mem- kinases suggests that its cytoplasmic domain could play an brane CD133 were linked to shorter survival, membrane important role in the regulation of its functions (Figure 1(a)). In particular, the phosphorylation of tyrosine- positivity only seems to confer the worst patient outcome. Furthermore, high membrane expression of CD133 was 828 and tyrosine-852 may regulate interaction of CD133 with SH2-domain containing proteins, which may be in- significantly associated with younger age at diagnosis and premenopausal status [26]. volved in a number of intracellular signaling events [33], including the activation of PI3K/Akt pathway [34–37]. Despite the general relationship between CD133 and breast tumor malignancy, some controversies concern the At variance with other solid tumors, little is known about the signaling associated to CD133 in breast cancer cells significance of CD133 in tumors with a triple negative phenotype (TNBC), in which CD133 is strongly hypo- (Figure 2). Interestingly, the almost totality of the data on breast tumors correlate CD133 with molecules involved in methylated with respect to other breast cancer subtypes cell motility and invasion, suggesting a direct role of PROM1 [27]. A strong negative correlation of CD133 levels with clinical stage of TNBC tumors was firstly observed by Zhao in modulating the potential malignancy of breast tumors. A role of CD133 in regulating the migration rate of breast et al. [28], and the use of CD133 to detect circulating tumor cells in TNBC patients ratified its role in prognosis of this cancer cells was firstly revealed in a murine model and involved c-Met and STAT3, both downstream to the Wnt breast cancer subtype [29]. Still in TNBC, Cantile et al. suggested that poor prognosis is possibly due to a nuclear signaling and responsible of cancer invasion and metastasis [38]. A peculiar role of CD133 in the direct modulation of mislocalization of CD133, which normally shows a membrane, and more sporadically cytoplasmic, localiza- motility and invasive potential of breast tumor cells was demonstrated in the TNBC-derived MDA-MB-231cell line tion [30]. In contrast to all the previous experimental evidences, Collina et al., who described a prevalent cyto- that comprises a small cellular subset expressing high levels of CD133 at both membrane and cytoplasm levels. Re- plasmic expression of CD133, failed to reveal statistical markably, the CD133 high cells showed lower proliferation association of CD133 expression with TNBCs patients’ survival [31]. )is discordance may be at least in part [39], in accordance with the evidence of Di Bonito et al., indicating that only in TNBC, both CD133 mRNA and ascribed to the well-known problem that concerns the different antibodies used to detect CD133 by cytofluori- protein positively correlate with geminin, an inhibitor of cell cycle progression [40]. CD133 high cells also showed a larger metrical and immunohistochemical investigations [21], as well as to the absence of standardized criteria to define the adhesion area, consistent with a more differentiated phe- notype [39], according to the described role of CD133 in scores used for the quantification of the glycoprotein at membrane, cytoplasm, and nuclear level. regulating differentiation of normal mammary gland [10]. On the other hand, CD133 high cells exhibited greater in- A recent study performed with the Gene Expression- Based Outcome for Breast Cancer Online (GOBO) algo- vasion capability, suggestive of higher metastatic potential, in accordance with the positive correlation between CD133 rithm confirmed that CD133 mRNA is associated with and poor prognosis in breast cancer. At variance with other distant metastasis-free survival (DMFS) in patients with all 4 Journal of Oncology 4. CD133 as a Marker of Malignant Progression Hypoxia Induced by Low Oxygen Availability ATRA A crucial driving force in the progression towards a more aggressive and resistant tumor phenotype is the adaptation IL-6 PLC-β2 Notch1 of neoplastic cells to a state of reduced oxygen availability defined as hypoxia [47–52]. At least half of all solid tumors, HIF-1α including breast cancer, enclose hypoxic regions varying in Hur-MALAT1 amount and size, and recurring tumors often exhibit a hypoxic fraction higher than primary tumors [53]. Intra- CD133 tumoral hypoxia has been identified as an adverse prognostic Twist1 indicator independent of all the histopathological parame- Chemoresistance ters and, in breast cancer, as in many other solid cancers, low Geminin Vasculogenic mimicry Tm4 AdoHcyase oxygen availability has been reported as associated with a Wnt signaling clinically aggressive tumor behavior [54]. Autophagy (c-Met, STAT3) In solid tumors, including breast cancer, CD133 is EMT generally induced by low oxygen availability via upregula- cell motility Proliferation tion HIF-1α (Figures 1(b) and 2), even though only in colon invasion differentiation cancer cells a physical interaction of HIF-1α with the CD133 apoptosis promoter was demonstrated [55–58]. Once again, the almost Figure 2: Regulation and functional roles of CD133 in breast totality of the studies correlating CD133 with low oxygen cancer. Schematic summary of the main mechanisms regulating availability looked at PROM1 as a marker of CSCs, known to CD133 gene expression in breast cancer cells (green circles: positive increase under hypoxia [50]. regulators; red circles: negative regulators) and of cellular events In breast tumors, Currie et al. firstly associated the ex- directly targeted by CD133 and involved in breast cancer pression of CD133 with markers of hypoxia and/or tumor progression. microvasculature in invasive and noninvasive breast carci- noma [23] although most of the further studies correlating CD133 to low oxygen availability were performed in TNBC. studies, these data highlight the value of both the number of In MDA-MB-231-derived xenografts, CD133 cells with CD133 cells and the expression levels of the surface antigen, cancer stem cell characteristics were related to vasculogenic which at least in part may justify some discrepancies on the mimicry (VM) (Figure 2) and hypoxia induced by the described prognostic role of CD133 in breast tumors. antiangiogenic agent sunitinib [59]. In the same cell model, When MDA-MB-231 subpopulations expressing dif- only CD133 cells formed VM channels in Matrigel after ferent levels of CD133 were subjected to two-dimensional reoxygenation, suggesting that hypoxia accelerates VM by electrophoresis followed by mass spectrometry, specific stimulating the CSC population [60]. Again in TNBCs, protein signatures were found, including proteins known to chemoresistance was associated with higher numbers of be deregulated and to play crucial roles in breast cancer [39]. CD133/ALDH1 or CD133/CD146 coexpressing cells that As expected, the fastest CD133 low cells expressed lower were in a quiescent autophagic state related to hypoxia [61]. levels of proteins involved in cell cycle and apoptosis, and the A further correlation of CD133 with autophagy induced by most invasive CD133 high cells showed higher expression of low oxygen availability was performed in patient-derived proteins with an oncogenic/metastatic role. )e CD133- TNBC xenografts, in which hypoxia increased drug re- related proteins included the actin-binding protein tropo- sistance of CD133 cells, and the inhibition of the auto- myosin4 (Tm4), upregulated in highly metastatic breast phagic pathway reversed chemoresistance [61]. cancer cell lines and associated with lymph node metastasis More recent in vitro studies suggest that the effects of of breast tumors [41] and AdoHcyase (Figure 2), known to hypoxia on the expression of CD133 in breast tumor cells are play a key role in the control of DNA methylation [42] and in closely related to their phenotype, and particularly to their the regulation of cell cycle, apoptosis, and cellular differ- ER status. In fact, low oxygen availability seems to induce entiation of breast tumor cells [43]. Of note, the silencing of CD133 only in ER cells and mostly in cells belonging to the CD133 in CD133 high cells reduced invasiveness and ex- luminal A subtype [62]. At variance with experiments in pression of Tm4, ascertaining the existence of direct which hypoxia was pharmacologically induced in xenografts mechanisms by which CD133 can promote invasiveness of [60], no significant modifications of CD133 were revealed in TNBC-derived cells [39]. TNBC-derived cells cultured under low oxygen [62]. At the A relationship between CD133 and EMT markers was basis of this discrepancy could be the change of the gly- demonstrated in tumors cells from metastatic breast cancer cosylation status of CD133 induced by hypoxia, in turn patients. In particular, the concomitant overexpression of responsible of abnormal detection of the extracellular gly- N-cadherin and CD133 was revealed in both circulating cosylated AC133 epitope, as observed in glioma cells [63]. tumor cells [44, 45] and breast cancer specimens [46], even if Since hypoxia improves both the number of cells a significant correlation between the two molecules and expressing high levels of CD133 and the malignant potential patient’s prognosis was not fully demonstrated. Journal of Oncology 5 of the noninvasive MCF10DCIS cells [64], the increase of MDA-MB-231cells, in which overexpression of the PLC CD133 was considered a marker of malignant evolution significantly reduced both membrane-associated and cyto- plasmic levels of CD133, in parallel with the CD133-related induced by low oxygen availability in both noninvasive and low-invasive breast tumors. invasion capability [46]. In the same cell model, PLC-β2 regulates the amount of CD133 cells with stem-like fea- tures. In particular, overexpression of PLC-β2 reduced the 5. Regulation of CD133 Levels + + + number of CD44 /CD133 /EpCAM cells and proliferation + + and invasion capability of the CD133 /EpCAM cellular )e expression of CD133 is controlled by many extracellular subset [74]. and intracellular agents, and hypoxic tumor microenvi- A role of PLC-β2 in modulating CD133 expression was ronment and mitochondria dysfunctions seem to be the also demonstrated in breast tumor derived cells under main events modulating CD133 levels [2, 11]. In particular, hypoxia. In particular, culture at low oxygen availability hypoxia can improve the levels of the CD133 mRNA by reduced PLC-β2 amount and increased CD133 expression in acting at transcriptional level and can increase the recovery ER breast tumor cells. Counteracting the decrease of PLC- of the AC133 epitope, by regulating its glycosylation status β2 prevented the increase of CD133 induced by hypoxia and [58, 63]. significantly reduced the hypoxia-related accumulation of Apart from the hypoxia-related role of HIF-1α, there is a HIF-1α (Figure 2), a putative regulator of CD133 in this cell general agreement that the transcription factors that interact model [62]. )e same study demonstrated that PLC-β2 is not with CD133 promoters are tumor dependent [12]. For this modified by hypoxia in TNBC-derived cells, in which low reason, although substantial evidence assigns to the increase oxygen availability fails to induce CD133. On the other hand, of CD133 levels a crucial role in the malignant potential of its forced expression induced a decrease of the number of various solid tumors, the regulatory mechanisms that pro- CD133 cells, confirming, also in this breast tumor subtype, mote CD133 expression are still largely unknown in breast the role of PLC-β2 in downregulating CD133 [62]. cancer. )e relationship between CD133 cancer stem cells PLC-β2 is ectopically expressed and regulates the and the Notch signaling was shown in several tumors, in- number of cells expressing CD133 also in the noninvasive cluding breast cancer [65, 66], but only in gastric cancer MCF10DCIS cells [75]. In the same cell model, the ad- cells, the direct binding of Notch 1 with the promoter region ministration of all trans retinoic acid (ATRA), currently of CD133 was demonstrated [67]. In colon cancer and os- used in the management of acute promyelocytic leukemia teosarcoma, CD133 expression is negatively regulated by [76] in which it induces the expression of PLC-β2 [77], direct binding of p53 to a noncanonical p53-binding se- counteracts the effects of hypoxia on CD133 expression by quence in the CD133 promoter [68]. Moreover, TGFβ1 is up-modulating the PLC isozyme [64]. )ese data constitute able to regulate CD133 expression in hepatocellular carci- the first evidence that CD133 levels can be modulated by noma through inhibition of DNMT1 and DNMT3β ex- acting on specific signaling molecules and suggest that ag- pression [69] (Figure 1(b)). onists able to upmodulate PLC-β2 could counteract the Abnormal DNA methylation, usually reported in many CD133-related malignant properties in noninvasive and human cancers, seems to play a critical role in CD133 ex- invasive breast tumor cells. pression, and deregulation of the methylation status was proposed to be at the basis of increased CD133 expression in breast cancer. In particular, D’Anello and colleagues [70] 6. Conclusion reported that IL-6 induced loss of methylation at CD133 promoter enhancing CD133 gene transcription in basal-like )is review collects the data concerning the expression of breast cancer via an autocrine loop triggered by the in- CD133 in breast cancer in which this surface antigen is activation of p53. Moreover, in cells with a luminal A generally associated with a stem cell-like phenotype. In phenotype, but not in TNBC-derived cells, the expression of parallel with the role as a cancer stem cell marker, we CD133 was linked to MALAT1, one of the most widely reviewed the value of CD133 as a prognostic factor and studied long coding RNA in cancer development and indicator of malignant progression of breast tumors, progression, and to the RNA binding protein HuR highlighting its direct role in modulating invasive potential (Figure 1(b)). HuR/MALAT1 impact on CD133 gene ex- of breast tumor cells with a triple negative phenotype. We pression can regulate EMT features, suggesting that the also revised the mechanisms regulating CD133 gene ex- specific regulation of these molecules could control, at least pression in both noninvasive and invasive breast tumor cells, in part, the CD133-related tumor progression [71]. underlining experimental strategies capable to limit its ex- pression level that could constitute the basis for new ther- apeutic approaches to reduce malignancy and/or to prevent 5.1. PLC-β2 Regulates CD133 in Breast Cancer Cells. An progression of breast tumors. unexpected role in the regulation of CD133 mRNA in breast tumor cells was reported for the beta-2 isoform of PLC (PLC-β2) (Figure 2), poorly expressed in normal breast Conflicts of Interest tissues and upregulated in tumor cells, in which sustains motility of invasive cells [72, 73]. )e first evidence of a )e authors declare that there are no conflicts of interest direct regulation of CD133 by PLC-β2 was obtained in regarding the publication of this paper. 6 Journal of Oncology [15] M. H. Wright, A. M. Calcagno, C. D. Salcido, M. D. Carlson, Authors’ Contributions S. V. Ambudkar, and L. Varticovski, “Brca1 breast tumors + – + contain distinct CD44 /CD24 and CD133 cells with cancer Federica Brugnoli and Silvia Grassilli contributed equally to stem cell characteristics,” Breast Cancer Research, vol. 10, this article. no. 1, p. R10, 2008. [16] A. K. Croker, D. Goodale, J. Chu et al., “High aldehyde de- Acknowledgments hydrogenase and expression of cancer stem cell markers se- lects for breast cancer cells with enhanced malignant and )is work was supported by grants from the University of metastatic ability,” Journal of Cellular and Molecular Medi- Ferrara (Italy) to VB and SC and from Unife-CCIAA cine, vol. 13, no. 8b, pp. 2236–2252, 2009. (Ferrara, Italy) to VB. [17] M. J. Meyer, J. M. Fleming, A. F. Lin, S. A. Hussnain, pos hi E. Ginsburg, and B. K. Vonderhaar, “CD44 CD49f CD133/ References hi 2 defines xenograft-initiating cells in estrogen receptor- negative breast cancer,” Cancer Research, vol. 70, no. 11, [1] D. Corbeil, K. Roper, C. A. Fargeas, A. Joester, and pp. 4624–4633, 2010. W. B. Huttner, “Prominin: a story of cholesterol, plasma [18] S. Borgna, M. Armellin, A. di Gennaro, R. Maestro, and membrane protrusions and human pathology,” Traffic, vol. 2, M. Santarosa, “Mesenchymal traits are selected along with no. 2, pp. 82–91, 2001. stem features in breast cancer cells grown as mammospheres,” [2] P. M. Glumac and A. M. LeBeau, “)e role of CD133 in Cell Cycle, vol. 11, no. 22, pp. 4242–4251, 2012. cancer: a concise review,” Clinical and Translational Medicine, [19] W. Zheng, B. Duan, Q. Zhang et al., “Vitamin D-induced vol. 7, no. 1, p. 18, 2018. vitamin D receptor expression induces tamoxifen sensitivity [3] A. H. Yin, S. Miraglia, E. D. Zanjani et al., “AC133, a novel in MCF-7 stem cells via suppression of Wnt/β-catenin sig- marker for human hematopoietic stem and progenitor cells,” naling,” Bioscience Reports, vol. 38, no. 6, Article ID Blood, vol. 90, no. 12, pp. 5002–5012, 1997. BSR20180595, 2018. [4] P. Salven, S. Mustjoki, R. Alitalo, K. Alitalo, and S. Rafii, [20] R. V. Oliveira, V. B. Souza, P. C. Souza et al., “Detection of “VEGFR-3 and CD133 identify a population of CD34+ putative stem-cell markers in invasive ductal carcinoma of the lymphatic/vascular endothelial precursor cells,” Blood, breast by immunohistochemistry: does it improve prognostic/ vol. 101, no. 1, pp. 168–172, 2003. predictive assessments?,” Applied Immunohistochemistry & [5] C. A. Fargeas, A.-V. Fonseca, W. B. Huttner, and D. Corbeil, Molecular Morphology, vol. 26, no. 10, pp. 760–768, 2018. “Prominin-1 (CD133): from progenitor cells to human dis- [21] P. Grosse-Gehling, C. A. Fargeas, C. Dittfeld et al., “CD133 as eases,” Future Lipidology, vol. 1, no. 2, pp. 213–225, 2006. a biomarker for putative cancer stem cells in solid tumours: [6] C. A. Fargeas, A. Joester, E. Missol-Kolka, A. Hellwig, limitations, problems and challenges,” 2e Journal of Pa- W. B. Huttner, and D. Corbeil, “Identification of novel thology, vol. 229, no. 3, pp. 355–378, 2013. Prominin-1/CD133 splice variants with alternative C-termini [22] Q. Liu, J. G. Li, X. Y. Zheng, F. Jin, and H. T. Dong, “Ex- and their expression in epididymis and testis,” Journal of Cell pression of CD133, PAX2, ESA, and GPR30 in invasive ductal Science, vol. 117, no. 18, pp. 4301–4311, 2004. breast carcinomas,” Chinese Medical Journal, vol. 122, no. 22, [7] G. D. Richardson, C. N. Robson, S. H. Lang, D. E. Neal, pp. 2763–2769, 2009. N. J. Maitland, and A. T. Collins, “CD133, a novel marker for [23] M. J. Currie, B. E. Beardsley, G. C. Harris et al., “Immuno- human prostatic epithelial stem cells,” Journal of Cell Science, histochemical analysis of cancer stem cell markers in invasive vol. 117, no. 16, pp. 3539–3545, 2004. breast carcinoma and associated ductal carcinoma in situ: [8] M. Florek, M. Haase, A.-M. Marzesco et al., “Prominin-1/ relationships with markers of tumor hypoxia and micro- CD133, a neural and hematopoietic stem cell marker, is vascularity,” Human Pathology, vol. 44, no. 3, pp. 402–411, expressed in adult human differentiated cells and certain types of kidney cancer,” Cell and Tissue Research, vol. 319, no. 1, [24] P. Xia, “CD133 mRNA may be a suitable prognostic marker pp. 15–26, 2005. for human breast cancer,” Stem Cell Investigation, vol. 4, [9] H. T. Hassan, X. Zhai, and J. A. Goodacre, “CD133 stem cells no. 11, p. 87, 2017. in adult human brain,” Journal of Neuro-Oncology, vol. 89, [25] L. Han, X. Gao, X. Gu et al., “Prognostic significance of cancer no. 2, pp. 247-248, 2008. stem cell marker CD133 expression in breast cancer,” In- [10] L. H. Anderson, C. A. Boulanger, G. H. Smith, P. Carmeliet, ternational Journal of Clinical and Experimental Medicine, and C. J. Watson, “Stem cell marker prominin-1 regulates vol. 10, no. 3, pp. 4829–4837, 2017. branching morphogenesis, but not regenerative capacity, in [26] C. Joseph, M. Arshad, S. Kurozomi et al., “Overexpression of the mammary gland,” Developmental Dynamics, vol. 240, the cancer stem cell marker CD133 confers a poor prognosis no. 3, pp. 674–681, 2011. in invasive breast cancer,” Breast Cancer Research and [11] A. Barzegar Behrooz, A. Syahir, and S. Ahmad, “CD133: Treatment, vol. 174, no. 2, pp. 387–399, 2019. beyond a cancer stem cell biomarker,” Journal of Drug Tar- [27] N. Kagara, K. T. Huynh, C. Kuo et al., “Epigenetic regulation geting, vol. 17, pp. 1–13, 2018. [12] G. Y. Liou, “CD133 as a regulator of cancer metastasis through of cancer stem cell genes in triple-negative breast cancer,” 2e American Journal of Pathology, vol. 181, no. 1, pp. 257–267, the cancer stem cells,” 2e International Journal of Bio- chemistry & Cell Biology, vol. 106, pp. 1–7, 2019. 2012. [28] P. Zhao, Y. Lu, X. Jiang, and X. Li, “Clinicopathological [13] M. Najafi, B. Farhood, and K. Mortezaee, “Cancer stem cells (CSCs) in cancer progression and therapy,” Journal of Cellular significance and prognostic value of CD133 expression in triple-negative breast carcinoma,” Cancer Science, vol. 102, Physiology, vol. 234, no. 6, pp. 8381–8395, 2019. [14] A. Lorico and G. Rappa, “Phenotypic heterogeneity of breast no. 5, pp. 1107–1111, 2011. [29] R. Nadal, F. G. Ortega, M. Salido et al., “CD133 expression in cancer stem cells,” Journal of Oncology, vol. 2011, Article ID 135039, 6 pages, 2011. circulating tumor cells from breast cancer patients: potential Journal of Oncology 7 role in resistance to chemotherapy,” International Journal of tumor cells of metastatic breast cancer patients,” Breast Cancer, vol. 133, no. 10, pp. 2398–2407, 2013. Cancer Research, vol. 11, no. 4, p. R46, 2009. [30] M. Cantile, F. Collina, M. D’Aiuto et al., “Nuclear localization [45] A. J. Armstrong, M. S. Marengo, S. Oltean et al., “Circulating of cancer stem cell marker CD133 in triple-negative breast tumor cells from patients with advanced prostate and breast cancer: a case report,” Tumori Journal, vol. 99, no. 5, cancer display both epithelial and mesenchymal markers,” pp. e245–e250, 2013. Molecular Cancer Research, vol. 9, no. 8, pp. 997–1007, 2011. [31] F. Collina, M. Di Bonito, V. Li Bergolis et al., “Prognostic [46] C. Bock, C. Kuhn, N. Ditsch et al., “Strong correlation be- value of cancer stem cells markers in triple-negative breast tween N-cadherin and CD133 in breast cancer: role of both cancer,” BioMed Research International, vol. 2015, Article ID markers in metastatic events,” Journal of Cancer Research and 158682, 10 pages, 2015. Clinical Oncology, vol. 140, no. 11, pp. 1873–1881, 2014. [32] N. Aomatsu, M. Yashiro, S. Kashiwagi et al., “CD133 is a [47] L. Schito and G. L. Semenza, “Hypoxia-Inducible factors: useful surrogate marker for predicting chemosensitivity to master regulators of cancer progression,” Trends in Cancer, neoadjuvant chemotherapy in breast cancer,” PLoS One, vol. 2, no. 12, pp. 758–770, 2016. vol. 7, no. 9, Article ID e45865, 2012. [48] K. R. Luoto, R. Kumareswaran, and R. G. Bristow, “Tumor [33] D. Boivin, D. Labbé, N. Fontaine et al., “)e stem cell marker hypoxia as a driving force in genetic instability,” Genome CD133 (Prominin-1) is phosphorylated on cytoplasmic ty- Integrity, vol. 4, no. 1, p. 5, 2013. rosine-828 and tyrosine-852 by Src and Fyn tyrosine kinases,” [49] S. Chouaib, M. Z. Noman, K. Kosmatopoulos, and Biochemistry, vol. 48, no. 18, pp. 3998–4007, 2009. M. A. Curran, “Hypoxic stress: obstacles and opportunities for [34] A. Dubrovska, S. Kim, R. J. Salamone et al., “)e role of innovative immunotherapy of cancer,” Oncogene, vol. 36, PTEN/Akt/PI3K signaling in the maintenance and viability of no. 4, pp. 439–445, 2017. prostate cancer stem-like cell populations,” Proceedings of the [50] A. Mohyeldin, T. Garzon-Muvdi, and A. Quiñones-Hinojosa, National Academy of Sciences, vol. 106, no. 1, pp. 268–273, “Oxygen in stem cell biology: a critical component of the stem cell niche,” Cell Stem Cell, vol. 7, no. 2, pp. 150–161, 2010. [35] H. Sartelet, T. Imbriglio, C. Nyalendo et al., “CD133 ex- [51] E. B. Rankin, J.-M. Nam, and A. J. Giaccia, “Hypoxia: sig- pression is associated with poor outcome in neuroblastoma naling the metastatic cascade,” Trends in Cancer, vol. 2, no. 6, via chemoresistance mediated by the AKT pathway,” Histo- pp. 295–304, 2016. pathology, vol. 60, no. 7, pp. 1144–1155, 2012. [52] S. Marx, M. Van Gysel, A. Breuer et al., “Potentialization of [36] Y. Wei, Y. Jiang, F. Zou et al., “Activation of PI3K/Akt anticancer agents by identification of new chemosensitizers pathway by CD133-p85 interaction promotes tumorigenic active under hypoxia,” Biochem Pharmacol, vol. 162, capacity of glioma stem cells,” Proceedings of the National pp. 224–236, 2019. Academy of Sciences, vol. 110, no. 17, pp. 6829–6834, 2013. [53] V. Bhandari, C. Hoey, L. Y. Liu et al., “Molecular landmarks of [37] J. U. Schmohl and D. A. Vallera, “CD133, selectively targeting tumor hypoxia across cancer types,” Nature Genetics, vol. 51, the root of cancer,” Toxins, vol. 8, 2016. no. 2, pp. 308–318, 2019. [38] J. Sun, C. Zhang, G. Liu et al., “A novel mouse CD133 [54] J. C. Walsh, A. Lebedev, E. Aten, K. Madsen, L. Marciano, and binding-peptide screened by phage display inhibits cancer cell H. C. Kolb, “)e clinical importance of assessing tumor motility in vitro,” Clinical & Experimental Metastasis, vol. 29, hypoxia: relationship of tumor hypoxia to prognosis and no. 3, pp. 185–196, 2012. therapeutic opportunities,” Antioxidants & Redox Signaling, [39] F. Brugnoli, S. Grassilli, M. Piazzi et al., “In triple negative vol. 21, no. 10, pp. 1516–1554, 2014. breast tumor cells, PLC-β2 promotes the conversion of high low [55] A. Soeda, M. Park, D. Lee et al., “Hypoxia promotes expansion CD133 to CD133 phenotype and reduces the CD133- of the CD133-positive glioma stem cells through activation of related invasiveness,” Molecular Cancer, vol. 12, no. 1, p. 165, HIF-1α,” Oncogene, vol. 28, no. 45, pp. 3949–3959, 2009. [56] L. P. Schwab, D. L. Peacock, D. Majumdar et al., “Hypoxia- [40] M. Di Bonito, M. Cantile, F. Collina et al., “Overexpression of inducible factor 1α promotes primary tumor growth and cell cycle progression inhibitor geminin is associated with tumor-initiating cell activity in breast cancer,” Breast Cancer tumor stem-like phenotype of triple-negative breast cancer,” Research, vol. 14, no. 1, p. R6, 2012. Journal of Breast Cancer, vol. 15, no. 2, pp. 162–171, 2012. [57] K. Maeda, Q. Ding, M. Yoshimitsu et al., “CD133 modulate [41] H. Li, F. Li, Z. M. Qian, and H. Sun, “Structure and topology of HIF-1alpha expression under hypoxia in emt phenotype the transmembrane domain 4 of the divalent metal trans- pancreatic cancer stem-like cells,” International Journal of porter in membrane-mimetic environments,” European Molecular Sciences, vol. 17, no. 7, Article ID E1025, 2016. Journal of Biochemistry, vol. 271, no. 10, pp. 1938–1951, 2004. [58] S. Ohnishi, O. Maehara, K. Nakagawa et al., “hypoxia-in- [42] H. Gellekink, M. d. Heijer, L. A. J. Kluijtmans, and H. J. Blom, ducible factors activate CD133 promoter through ETS family “Effect of genetic variation in the human S-adenosylhomo- transcription factors,” PLoS One, vol. 8, no. 6, Article ID cysteine hydrolase gene on total homocysteine concentrations e66255, 2013. and risk of recurrent venous thrombosis,” European Journal of [59] T. J. Liu, B. C. Sun, X. L. Zhao et al., “CD133 cells with cancer Human Genetics, vol. 12, no. 11, pp. 942–948, 2004. stem cell characteristics associates with vasculogenic mimicry [43] A. Hayden, P. W. M. Johnson, G. Packham, and S. J. Crabb, in triple-negative breast cancer,” Oncogene, vol. 32, no. 5, “S-adenosylhomocysteine hydrolase inhibition by 3-deaza- pp. 544–553, 2013. neplanocin A analogues induces anti-cancer effects in breast [60] D. Zhang, B. Sun, X. Zhao et al., “Twist1 expression induced cancer cell lines and synergy with both histone deacetylase by sunitinib accelerates tumor cell vasculogenic mimicry by and HER2 inhibition,” Breast Cancer Research and Treatment, vol. 127, no. 1, pp. 109–119, 2011. increasing the population of CD133 cells in triple-negative [44] B. Aktas, M. Tewes, T. Fehm, S. Hauch, R. Kimmig, and breast cancer,” Molecular Cancer, vol. 13, no. 1, p. 207, 2014. [61] G. Bousquet, M. El Bouchtaoui, T. Sophie et al., “Targeting S. Kasimir-Bauer, “Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating autophagic cancer stem-cells to reverse chemoresistance in 8 Journal of Oncology human triple negative breast cancer,” Oncotarget, vol. 8, [77] V. Bertagnolo, M. Marchisio, S. Pierpaoli et al., “Selective up- no. 21, pp. 35205–35221, 2017. regulation of phospholipase C-β2 during granulocytic dif- [62] F. Brugnoli, S. Grassilli, Y. Al-Qassab, S. Capitani, and ferentiation of normal and leukemic hematopoietic pro- V. Bertagnolo, “PLC-β2 is modulated by low oxygen avail- genitors,” Journal of Leukocyte Biology, vol. 71, pp. 957–965, ability in breast tumor cells and plays a phenotype dependent role in their hypoxia-related malignant potential,” Molecular Carcinogenesis, vol. 55, no. 12, pp. 2210–2221, 2016. [63] K. S. Lehnus, L. K. Donovan, X. Huang et al., “CD133 gly- cosylation is enhanced by hypoxia in cultured glioma stem cells,” International Journal of Oncology, vol. 42, no. 3, pp. 1011–1017, 2013. [64] Y. Al-Qassab, S. Grassilli, F. Brugnoli, F. Vezzali, S. Capitani, and V. Bertagnolo, “Protective role of all-trans retinoic acid (ATRA) against hypoxia-induced malignant potential of non- invasive breast tumor derived cells,” BMC Cancer, vol. 18, no. 1, p. 1194, 2018. [65] P. Sansone, M. Berishaj, V. K. Rajasekhar et al., “Evolution of cancer stem-like cells in endocrine-resistant metastatic breast cancers is mediated by stromal microvesicles,” Cancer Re- search, vol. 77, no. 8, pp. 1927–1941, 2017. [66] S. K. Saha, H. Y. Choi, B. W. Kim et al., “KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB- dependent NOTCH signaling pathway and breast cancer properties,” Oncogene, vol. 36, no. 3, pp. 332–349, 2017. [67] H. Konishi, N. Asano, A. Imatani et al., “Notch1 directly induced CD133 expression in human diffuse type gastric cancers,” Oncotarget, vol. 7, pp. 56598–56607, 2016. [68] E. K. Park, J. C. Lee, J. W. Park et al., “Transcriptional re- pression of cancer stem cell marker CD133 by tumor sup- pressor p53,” Cell Death & Disease, vol. 6, no. 11, Article ID e1964, 2015. [69] H. You, W. Ding, and C. B. Rountree, “Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-β,” Hepatology, vol. 51, no. 5, pp. 1635–1644, 2010. [70] L. D’Anello, P. Sansone, G. Storci et al., “Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells,” Molecular Cancer, vol. 9, no. 1, p. 300, [71] E. Latorre, S. Carelli, I. Raimondi et al., “)e ribonucleic complex hur-MALAT1 represses CD133 expression and suppresses epithelial-mesenchymal transition in breast can- cer,” Cancer Research, vol. 76, no. 9, pp. 2626–2636, 2016. [72] V. Bertagnolo, M. Benedusi, P. Querzoli et al., “PLC-beta2 is highly expressed in breast cancer and is associated with a poor outcome: a study tissue microarrays,” International Journal of Oncology, vol. 28, no. 4, pp. 863–872, 2006. [73] V. Bertagnolo, M. Benedusi, F. Brugnoli et al., “Phospholipase C-β2 promotes mitosis and migration of human breast cancer-derived cells,” Carcinogenesis, vol. 28, no. 8, pp. 1638–1645, 2007. [74] F. Brugnoli, S. Grassilli, P. Lanuti et al., “Up-modulation of PLC-β2 reduces the number and malignancy of triple-neg- + + ative breast tumor cells with a CD133 /EpCAM phenotype: a promising target for preventing progression of TNBC,” BMC Cancer, vol. 17, no. 1, p. 617, 2017. [75] V. Bertagnolo, S. Grassilli, S. Volinia et al., “Ectopic ex- pression of PLC-β2 in non-invasive breast tumor cells plays a protective role against malignant progression and is corre- lated with the deregulation of miR-146a,” Molecular Carci- nogenesis, vol. 58, no. 5, 2018. [76] S. Kayser, R. F. Schlenk, and U. Platzbecker, “Management of patients with acute promyelocytic leukemia,” Leukemia, vol. 32, no. 6, pp. 1277–1294, 2018. 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