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

## TL;DR

HER2 and HER3 signaling alters FOXA1 activity, reducing hormone therapy effectiveness in breast cancer.

## Contribution

Discovery of HER2/HER3-driven FOXA1 deacetylation as a novel mechanism of hormone therapy resistance.

## Key findings

- High HER2 levels increase FOXA1 chromatin binding while decreasing ER occupancy.
- HER2/HER3 signaling promotes FOXA1 deacetylation via HDAC2, enhancing ER-independent chromatin binding.
- FOXA1 deacetylation leads to reduced sensitivity to ER-targeted therapies in breast cancer models.

## 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 hormone therapy. In a luminal breast cancer patient-derived xenograft model, HER2/HER3 signaling increased FOXA1 chromatin binding and reduced sensitivity to ER-targeted treatment. We identify HDAC2 as a key deacetylase modulating FOXA1 acetylation and partially mediating the effects of HER2/HER3 signaling. Altogether, our findings highlight the significance of FOXA1 acetylation, regulated by the HER2/HER3–HDAC2–FOXA1 axis, in controlling FOXA1 chromatin binding and shaping breast cancer progression and therapy response. These insights may inform future therapeutic strategies.

Graphical Abstract