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Updated: Jan 10, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
PBRM1-Dependent PBAF Targeting is Required for EMT and Metastasis in Breast Cancer
Abstract:
SWI/SNF chromatin remodelers utilize ATP to mobilize nucleosomes on DNA and are represented by three biochemically distinct subcomplexes, the more abundant cBAF and the less abundant PBAF and GBAF subcomplexes. Patient mutations and genetic studies have identified important roles for PBAF subunits in development and disease; however, relating PBAF-mediated phenotypes to biochemical function in chromatin regulation and gene expression has been challenging. Further complicating matters, cell-based systems often do not reflect the phenotypes and genotypes observed with PBAF mutations in vivo . Here we show that the PBRM1 subunit of PBAF is critical for the completion of TGFB1-mediated epithelial-mesenchymal transition of mammary cells in vitro as well as the metastasis of murine breast cancers in vivo. Using epigenomics to profile different stages of EMT, we find that PBRM1 is necessary for targeting PBAF to inducible promoters marked by H3K14ac alone. We further find that PBRM1 facilitates DNA accessibility at sites bound by TGFβ1-inducible transcription factors, such as Atf3, for the induction of genes involved in migration, cell survival, and inflammation. Our model allows us to separate constitutive vs inducible gene expression to help explain some of the context-dependent phenotypes observed with PBRM1 deletion. In addition, we provide evidence that while PBRM1 deletions can promote the initiation of certain cancers in early stages, PBAF may be a vulnerability in late-stage metastatic cancers.
Insights
The PBAF chromatin remodeler, specifically its PBRM1 subunit, is crucial for breast cancer metastasis and epithelial-mesenchymal transition. PBRM1 targets specific gene promoters, influencing cell migration and survival, and may represent a therapeutic target in advanced cancers.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Biology
Background:
- SWI/SNF chromatin remodelers, including PBAF, regulate gene expression by mobilizing nucleosomes.
- PBAF subunit mutations are linked to developmental and disease phenotypes, but their biochemical functions remain unclear.
- In vivo phenotypes associated with PBAF mutations are not always replicated in cell-based systems.
Purpose of the Study:
- To investigate the role of the PBAF subunit PBRM1 in TGFB1-mediated epithelial-mesenchymal transition (EMT) and breast cancer metastasis.
- To elucidate the mechanisms by which PBRM1 influences gene expression during EMT.
- To explore the dual role of PBAF in cancer initiation and progression.
Main Methods:
- Epigenomic profiling of mammary cells during EMT.
- In vitro and in vivo studies of PBRM1's role in EMT and metastasis.
- Analysis of PBRM1's targeting of inducible promoters and its effect on DNA accessibility.
Main Results:
- PBRM1 is essential for TGFB1-induced EMT in mammary cells and metastasis of murine breast cancers.
- PBRM1 directs PBAF to inducible promoters marked by H3K14ac and facilitates DNA accessibility for TGFβ1-inducible transcription factors.
- PBRM1 deletion influences both constitutive and inducible gene expression, explaining context-dependent phenotypes.
Conclusions:
- PBRM1 is a critical regulator of EMT and breast cancer metastasis, acting by modulating chromatin accessibility at specific gene loci.
- PBAF's role in gene regulation during EMT provides insights into context-dependent phenotypes observed in PBRM1-deficient cells.
- PBAF may serve as a vulnerability in late-stage metastatic cancers, despite PBRM1 deletions potentially promoting early-stage cancer initiation.
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