The harmonized activities of HER2-HER3 heterodimer and deacetylated FOXA1 evade hormone response by regulating FOXA1 chromatin binding.

ABSTRACT: FOXA1 is a key transcription factor that mediates the effects of estrogen receptor (ER) and HER2 signaling in breast cancer. However, the mechanisms underlying FOXA1 regulation by HER2 and ER remain poorly understood. Here, we investigated FOXA1 regulation in cells with varying HER2 levels and its impact on endocrine therapy response. Chromatin interaction analyses revealed that high HER2 levels enhance FOXA1 binding to chromatin regions while reducing ER occupancy. Mechanistically, FOXA1 is acetylated by the histone acetyltransferase EP300 at the WD1 domain in ER-positive cells, attenuating its DNA binding at HER2-induced chromatin regions. Conversely, FOXA1 deacetylation-triggered by HER2/HER3 activation-increases its binding to ER-independent regions and promotes insensitivity to hormon

SUBMITTER: Wang S 

PROVIDER: S-EPMC12611346 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature