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Transcription Factor Networks in Invasion-Promoting Breast Carcinoma-Associated Fibroblasts

Transcription Factor Networks in Invasion-Promoting Breast Carcinoma-Associated Fibroblasts Carcinoma-associated fibroblasts (CAFs) contribute to both tumor growth and cancer progression. In this report, we applied an emerging transcription factor (TF) activity array to fibroblasts to capture the activity of the intracellular signaling network and to define a signature that distinguishes mammary CAFs from normal mammary fibroblasts. Normal fibroblasts that restrained cancer cell invasion developed into an invasion-promoting CAF phenotype through exposure to conditioned medium from MDA-MB-231 breast cancer cells. A myofibroblast-like CAF cell line expressing high levels of smooth muscle actin was compared to normal mammary fibroblasts before and after induction. Comparison of TF activity profiles for all three fibroblast types identified a TF activity signature common to CAFs which included activation of reporters for TFs ELK1, GATA1, retinoic acid receptor (RAR), serum response factor (SRF), and vitamin D receptor (VDR). Additionally, CAFs resembling myofibroblasts, relative to normal fibroblasts, had elevated activation corresponding to NF-kappaB, RUNX2, and YY1, and distinct activity patterns for several differentiation-related TF reporters. Induction of CAFs by exposure of normal fibroblasts to conditioned medium from MDA-MB-231 cells resulted in increased activation of reporters for HIF1, several STAT TFs, and proliferation-related TFs such as AP1. Myofibroblast-like CAFs and induced normal mammary fibroblasts promoted invasion of breast cancer cells by distinct mechanisms, consistent with their distinct patterns of TF activation. The TF activity profiles of CAF subtypes provide an overview of intracellular signaling associated with the induction of a pro-invasive stroma, and provide a mechanistic link between the microenvironmental stimuli and phenotypic response. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Microenvironment Springer Journals

Transcription Factor Networks in Invasion-Promoting Breast Carcinoma-Associated Fibroblasts

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References (70)

Publisher
Springer Journals
Copyright
Copyright © 2012 by Springer Science+Business Media B.V.
Subject
Biomedicine; Cancer Research; Oncology; Immunology; Cell Biology; Biochemistry, general; Biomedicine general
ISSN
1875-2292
eISSN
1875-2284
DOI
10.1007/s12307-012-0121-z
pmid
23090154
Publisher site
See Article on Publisher Site

Abstract

Carcinoma-associated fibroblasts (CAFs) contribute to both tumor growth and cancer progression. In this report, we applied an emerging transcription factor (TF) activity array to fibroblasts to capture the activity of the intracellular signaling network and to define a signature that distinguishes mammary CAFs from normal mammary fibroblasts. Normal fibroblasts that restrained cancer cell invasion developed into an invasion-promoting CAF phenotype through exposure to conditioned medium from MDA-MB-231 breast cancer cells. A myofibroblast-like CAF cell line expressing high levels of smooth muscle actin was compared to normal mammary fibroblasts before and after induction. Comparison of TF activity profiles for all three fibroblast types identified a TF activity signature common to CAFs which included activation of reporters for TFs ELK1, GATA1, retinoic acid receptor (RAR), serum response factor (SRF), and vitamin D receptor (VDR). Additionally, CAFs resembling myofibroblasts, relative to normal fibroblasts, had elevated activation corresponding to NF-kappaB, RUNX2, and YY1, and distinct activity patterns for several differentiation-related TF reporters. Induction of CAFs by exposure of normal fibroblasts to conditioned medium from MDA-MB-231 cells resulted in increased activation of reporters for HIF1, several STAT TFs, and proliferation-related TFs such as AP1. Myofibroblast-like CAFs and induced normal mammary fibroblasts promoted invasion of breast cancer cells by distinct mechanisms, consistent with their distinct patterns of TF activation. The TF activity profiles of CAF subtypes provide an overview of intracellular signaling associated with the induction of a pro-invasive stroma, and provide a mechanistic link between the microenvironmental stimuli and phenotypic response.

Journal

Cancer Microenvironment – Springer Journals

Published: Oct 23, 2012

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