FOXA1 ChIP-Seq in patient derived xenografts (PDX), MCF7 and BT474 cell lines

FOXA1 is a critical transcription factor involved in estrogen receptor (ER) and HER2 signaling of breast cancers. Yet, the precise regulation of FOXA1 by HER2 or ER remains unknown. Now, we investigated the regulation of FOXA1 in cells with varying levels of HER2 and its impact on endocrine treatment. The analysis of chromatin interactions unveiled that high HER2 level enhanced FOXA1 binding to chromatin regions while reducing ER binding. Mechanistically, we discovered that FOXA1 undergoes acetylation by the enzyme EP300 at the WD1 domain in ER- positive cells, leading to attenuated DNA binding at HER2 induced chromatin regions. Furthermore, we revealed that deacetylated FOXA1 renders cells insensitive to endocrine therapy by increasing its binding to chromatin regions induced by HER2/HER3. In an in vivo mouse model, activation of HER2/HER3 was observed to result in heightened FOXA1 binding to chromatin and hormone insensitivity. Additionally, the histone deacetylase HDAC2 inhibition, influenced FOXA1 function and cell growth independently of ER. In summary, this study highlights the significance of FOXA1 acetylation, regulated by HER2 signaling and protein deacetylases, in determining FOXA1 binding to chromatin. These findings shed light on its impact on breast cancer growth and response to therapy, providing valuable insights for potential therapeutic strategies.