PBRM1-Dependent PBAF Targeting is Required for EMT and Metastasis in Breast Cancer

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.