Journal Article

The Transcription Factors Snail and Slug Activate the Transforming Growth Factor-Beta Signaling Pathway in Breast Cancer

Mav, Deepak, Dhasarathy, Archana, Phadke, Dhiral, Shah, Ruchir R., Wade, Paul A.

2011

Overview

The transcriptional repressors Snail and Slug are situated at the core of several signaling pathways proposed to mediate epithelial to mesenchymal transition or EMT, which has been implicated in tumor metastasis. EMT involves an alteration from an organized, epithelial cell structure to a mesenchymal, invasive and migratory phenotype. In order to obtain a global view of the impact of Snail and Slug expression, we performed a microarray experiment using the MCF-7 breast cancer cell line, which does not express detectable levels of Snail or Slug. MCF-7 cells were infected with Snail, Slug or control adenovirus, and RNA samples isolated at various time points were analyzed across all transcripts. Our analyses indicated that Snail and Slug regulate many genes in common, but also have distinct sets of gene targets. Gene set enrichment analyses indicated that Snail and Slug directed the transcriptome of MCF-7 cells from a luminal towards a more complex pattern that includes many features of the claudin-low breast cancer signature. Of particular interest, genes involved in the TGF-beta signaling pathway are upregulated, while genes responsible for a differentiated morphology are downregulated following Snail or Slug expression. Further we noticed increased histone acetylation at the promoter region of the transforming growth factor beta-receptor II (TGFBR2) gene following Snail or Slug expression. Inhibition of the TGF-beta signaling pathway using selective small-molecule inhibitors following Snail or Slug addition resulted in decreased cell migration with no impact on the repression of cell junction molecules by Snail and Slug. We propose that there are two regulatory modules embedded within EMT: one that involves repression of cell junction molecules, and the other involving cell migration via TGF-beta and/or other pathways.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetylation / Acetylation - drug effects / Adenoviruses / Analysis / Benzamides - pharmacology / Biology / Bone morphogenetic proteins / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Cancer metastasis / Cell cycle / Cell Differentiation - drug effects / Cell Line, Tumor / Cell migration / Cell Movement - drug effects / Collaboration / Cytology / Dioxoles - pharmacology / DNA binding proteins / DNA microarrays / Down-Regulation - drug effects / Environmental health / Epithelial cells / Epithelial-Mesenchymal Transition - drug effects / Female / Gene expression / Genes / Genetic Loci - genetics / Growth factors / Health sciences / Histones - metabolism / Humans / Intercellular Junctions - drug effects / Intercellular Junctions - metabolism / Invasiveness / Kinases / Laboratories / Mammary Glands, Human - drug effects / Mammary Glands, Human - metabolism / Mammary Glands, Human - pathology / Medical prognosis / Mesenchyme / Metastases / Metastasis / Morphogenesis / Phenotype / Protein Serine-Threonine Kinases - genetics / Proteins / Pyrazoles - pharmacology / Pyrroles - pharmacology / Receptor, Transforming Growth Factor-beta Type II / Receptors, Transforming Growth Factor beta - genetics / Repressors / Ribonucleic acid / RNA / RNA, Messenger - genetics / RNA, Messenger - metabolism / Signal transduction / Signal Transduction - drug effects / Signaling / Snail Family Transcription Factors / Snail protein / Stem cells / Substrate Specificity / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription, Genetic - drug effects / Transforming Growth Factor beta - antagonists & inhibitors / Transforming Growth Factor beta - metabolism / Transforming growth factor-b / Transforming growth factors / Tumors