The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

Sep 21, 2026

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Background: The androgen receptor (AR) acts as a tumor suppressor in estrogen receptor (ER) positive breast cancer, yet key determinants of AR genomic activity in breast context remain unclear. Herein, an unbiased chromatin immunoprecipitation-based proteomic approach identifies endogenous AR co-regulatory proteins in ER positive and negative models. Results: GATA3 is validated as an AR interacting factor, with DHT enhancing AR-GATA3 nuclear interactions and GATA3 chromatin enrichment at defined loci. Silencing GATA3 reduces AR-driven transactivation of co-occupied genes and induces luminal differentiation programs, validated in patient-derived xenografts.

LanguageEnglish

CategoryResearch & Report

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Reading Time1 h 11 min

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Abstract

Background

Results

Conclusions

Background

Hosseinzadeh etal. Genome Biology (2024) 25:44 [https://doi.org/10.1186/s13059-023-03161-y](https://doi.org/10.1186/s13059-023-03161-y) Genome Biology RESEARCH Open Access The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer Leila Hosseinzadeh 1, Zoya Kikhtyak 1, Geraldine Laven‑Law 1, Stephen M. Pederson 1, Caroline G. Puiu 1, Clive S. D’Santos2, Elgene Lim3, Jason S. Carroll2, Wayne D. Tilley 1, Amy R. Dwyer 1† and Theresa E. Hickey 1*† | †Amy R. Dwyer and Theresa E. Hickey are co‑senior authors and contributed equally to this work. | | --- | | *Correspondence: [theresa.hickey@adelaide.edu.au](theresa.hickey@adelaide.edu.au) | 1 Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia 2 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 3 Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia Abstract Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation‑based proteomic technique to identify endogenous AR interacting co‑regulatory proteins in ER positive and nega‑ tive models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA‑binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α‑dihydrotestosterone (DHT) increases nuclear AR‑GATA3 inter‑ actions, resulting in AR‑dependent enrichment of GATA3 chromatin binding at a sub‑ set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co‑occupied loci, indicating a co‑regulatory role for GATA3 in AR signaling. DHT‑induced AR/GATA3 binding coin‑ cides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are vali‑ dated in a patient‑derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR‑mediated growth inhibition in ER positive and ER negative breast cancer. Conclusions: AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function ofAR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer. Keywords: Androgen receptor, GATA3, Breast, Luminal lineage © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the mate‑ rial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://](http://)[ ](http://)[creativecommons.org/licenses/by/4.0/](creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publi)[. The Creative Commons Public Do

FAQs

How was the endogenous AR interaction landscape identified in this study?

The study used an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in breast cancer models.

What role does GATA3 play in AR signaling according to the results?

GATA3 was identified and validated as a novel AR interacting protein. DHT increases nuclear AR-GATA3 interactions, promotes AR-dependent GATA3 chromatin binding at specific loci, and silencing GATA3 reduces AR-driven transactivation of co-occupied genes.

Does the AR-GATA3 interaction depend on estrogen receptor status?

No. The conclusions state that AR and GATA3 interact to regulate luminal epithelial differentiation in breast cancer regardless of ER status, with association to growth inhibition in both ER positive and ER negative tumors.

Sep 21, 2026

Uploaded by Himbo