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Updated: Jan 11, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

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

Shixiong Wang1, Gemma Santacana-Font2, Darek Kedra2

  • 1Cell cycle regulation group, Institute of Biosciences (IBV), University of Oslo, Kristine Bonnevies hus, Blindernveien 31, 0371 Oslo, Norway.

Nucleic Acids Research
|November 12, 2025
PubMed

Insights

HER2 signaling impacts breast cancer by altering FOXA1 acetylation, affecting its DNA binding and response to endocrine therapy. This highlights a new therapeutic target involving the HER2/HER3-HDAC2-FOXA1 pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Estrogen receptor (ER) and HER2 signaling are crucial in breast cancer.
  • FOXA1 transcription factor plays a key role in mediating ER and HER2 effects.
  • Mechanisms of FOXA1 regulation by HER2 and ER are not fully understood.

Purpose of the Study:

  • Investigate FOXA1 regulation in breast cancer cells with varying HER2 levels.
  • Determine the impact of FOXA1 regulation on endocrine therapy response.
  • Elucidate the role of acetylation and deacetylation in FOXA1 function.

Main Methods:

  • Chromatin interaction analyses in cells with different HER2 levels.
  • Investigation of FOXA1 acetylation by EP300.
  • Analysis of FOXA1 deacetylation triggered by HER2/HER3 activation.
  • Utilized a luminal breast cancer patient-derived xenograft model.
  • Identified HDAC2 as a key deacetylase.

Main Results:

  • High HER2 levels increase FOXA1 chromatin binding and decrease ER occupancy.
  • FOXA1 acetylation by EP300 attenuates DNA binding at HER2-induced regions.
  • FOXA1 deacetylation by HER2/HER3 activation increases binding to ER-independent regions, promoting therapy insensitivity.
  • HER2/HER3 signaling reduced sensitivity to ER-targeted treatment in a xenograft model.
  • HDAC2 modulates FOXA1 acetylation, mediating HER2/HER3 signaling effects.

Conclusions:

  • FOXA1 acetylation, regulated by the HER2/HER3-HDAC2-FOXA1 axis, controls FOXA1 chromatin binding.
  • This axis significantly influences breast cancer progression and response to endocrine therapy.
  • Findings offer potential new therapeutic strategies targeting this pathway.

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