Yu Bai: Elucidation of mechanisms in modulation of signaling by transforming growth factor-β (TGF-β) in breast cancer

Abstract

The cytokine transforming growth factor-β (TGF-β) is overexpressed in most advanced solid cancers, and it has a biphasic role in tumor progres-sion. Initially, TGF-β acts as a tumor suppressor since it inhibits the prolif-eration and promotes apoptosis of most cell types. However, in advanced cancers, TGF-β acts as a tumor promoter, which includes effects on the tumor cells, e.g. promotion of epithelial-mesenchymal transition (EMT), which is connected with increased invasiveness and metastasis, as well as effects on non-tumor cells. 

Breast cancer, the most commonly diagnosed cancer in women. Given the importance of TGF-β in regulating both tumor suppression and promotion, understanding its precise role in breast cancer could offer new opportunities for therapeutic intervention, particularly in developing treatments that can selectively block the tumor-promoting effects of TGF-β without disrupting its normal physiological functions.

In this study, we explored the mechanisms by which the transcription factor ΔNp63, the epigenetic regulator chromodomain helicase DNA binding protein 4 (CHD4), the Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), and integrin-αvβ5, influence TGF-β signaling and how these factors contribute to breast cancer progression.

Paper I demonstrated that TGF-β, through the activation of SMAD2/3, leads to the dissociation of ΔNp63 from the NURD or NCOR/SMRT histone deacetylation complexes. while promoting the formation of ΔNp63-p300 complexes, which alters histone acetylation levels and affects ΔNp63-dependent transcriptional outcomes.

Paper II showed that ROCK1 and ROCK2 have opposing effects on TGF-β-SMAD3/4 transcriptional activity. ROCK1 inhibits, while ROCK2 stimulates this activity, both in a kinase-dependent manner. Consistent with these findings, depletion of ROCK1 enhances TGF-β-induced invasion in breast cancer cells, whereas ROCK2 depletion reduces invasion.

Paper III revealed that CHD4 knock-out significantly increases CAGA12-GFP activity in MDA-MB-231 cells, with similar results observed in other breast cancer subtypes, underscoring the broad relevance of this finding. CHD4 is primarily localized in the nucleus and interacted with SMAD3, to a lesser extent with SMAD2, but not with SMAD4, in a ligand-dependent manner.

Paper IV demonstrated that integrin-αvβ5 facilitates the activation of the MEK-ERK MAPK pathway, which in turn promotes the expression of AP-1 components, particularly FOS family members. This enhances the expression of a subset of TGF-β-inducible genes associated with migration and invasion, including LAMB3, WNT7B, MMP9, and IL-11.