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Updated: May 28, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast
Archana Dhasarathy1, Dhiral Phadke, Deepak Mav
1Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.
Abstract:
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.
Insights
Snail and Slug proteins drive epithelial to mesenchymal transition (EMT) in breast cancer cells, altering gene expression and promoting cell migration via TGF-beta signaling. This study reveals distinct regulatory roles for Snail and Slug in EMT.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Biology
Background:
- Snail and Slug are transcriptional repressors central to epithelial to mesenchymal transition (EMT), a process implicated in tumor metastasis.
- EMT transforms epithelial cells into invasive mesenchymal cells, facilitating cancer spread.
- Understanding Snail and Slug's global impact is crucial for deciphering EMT's role in cancer progression.
Purpose of the Study:
- To globally analyze the impact of Snail and Slug expression on gene regulation in breast cancer cells.
- To identify common and distinct gene targets regulated by Snail and Slug.
- To elucidate the molecular mechanisms underlying EMT, focusing on TGF-beta signaling and cell migration.
Main Methods:
- Microarray analysis of MCF-7 breast cancer cells engineered to express Snail, Slug, or control adenovirus.
- Gene set enrichment analysis to interpret transcriptomic data.
- Investigating histone acetylation at the TGFBR2 gene promoter.
- Inhibition of the TGF-beta signaling pathway to assess its role in cell migration.
Main Results:
- Snail and Slug share many gene targets but also possess unique targets, altering the transcriptome towards a claudin-low breast cancer signature.
- Genes in the TGF-beta signaling pathway were upregulated, while those promoting differentiated morphology were downregulated.
- Increased histone acetylation was observed at the TGFBR2 promoter upon Snail/Slug expression.
- Inhibiting TGF-beta signaling reduced cell migration without affecting the repression of cell junction molecules.
Conclusions:
- Snail and Slug orchestrate EMT through at least two distinct regulatory modules.
- One module involves repressing cell junction molecules, while the other promotes cell migration, potentially via TGF-beta signaling.
- These findings offer insights into EMT's complex regulatory network and its implications for breast cancer metastasis.
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