Context-Specific Effects o f TGF-b / SMAD 3 in Cancer Are Modulated by the Epigenome Graphical

Graphical Abstract Highlights d TGF-b has opposing effects in different breast-tumor-initiating cell (BTIC) types d Genomic SMAD3 binding patterns are similar in BTICs with opposing responses to TGF-b d BTIC type-specific epigenomes prime genes for regulation by TGF-b/SMAD3 d LBH, a type-specific TGF-b target, is essential for BTIC-promoting effects of TGF-b In Brief The TGF-b pathway uses transcriptional regulation through SMAD transcription factors to modulate cell-context-specific phenotypes. Tufegdzic Vidakovic et al. show that in breast-tumor-initiating cells (BTICs), type-specific DNA and histone modifications help determine whether the response to TGF-b is pro-oncogenic or tumor suppressive. These landscapes act both in synergy and independently of cell-type-specific SMAD3 binding to TGF-b target genes to modulate context-specific transcriptional regulation by TGF-b/ SMAD3. SUMMARY The transforming growth factor beta (TGF-b) signaling pathway exerts opposing effects on cancer cells, acting as either a tumor promoter or a tumor suppressor. Here, we show that these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGF-b signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-b are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC-suppressing contexts. Our data show cell-type-specific patterns of DNA and histone modifications provide a modulatory layer by determining accessibility of genes to regulation by TGF-b/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status and is crucial for TGF-b-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGF-b in cancer.