Oral Presentation 37th Lorne Cancer Conference 2025

Interaction between the androgen receptor and GATA3 promotes luminal differentiation in breast cancer regardless of estrogen receptor status (113949)

Theresa E Hickey 1
  1. Dame Roma Mitchell Cancer Research Laboratories, Dept. of Medicine, University of Adelaide, Adelaide, South Australia, Australia

Our published studies support a tumour suppressor role for androgen receptor (AR) signalling in estrogen receptor positive (ER+) breast cancers and use of a selective AR modulator to treat advanced ER+ disease1-4. Preclinical studies suggest AR may also sustain tumour suppressor activity in some breast cancers that lack ER5. AR is a ligand-activated DNA-binding transcription factor that interacts with a multiplicity of co-regulatory proteins to influence gene expression programs. Key factors that regulate AR genomic activity in a breast cancer context are largely unknown. Therefore, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting proteins in cell line models of AR+ER+HER2- (T-47D, ZR-75-1), AR+ER-HER2+ (MDA-MB-453) and AR+ER-HER2- (MFM223) breast cancer. The GATA3 transcription factor was identified and validated as a novel AR interacting protein in all four breast cancer models. AR activation with 5α-dihydrotestosterone (DHT) increased nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. DHT-induced AR-GATA3 loci were located near genes enriched for luminal differentiation pathways. Among these genes, up-regulation of EHF and KDM4B was observed in all cell line models and validated at the protein level. EHF and KDM4B are established master regulators of a breast epithelial cell lineage, and loss of either is associated with a basal phenotype and increased metastatic behaviour. AR-GATA3 interaction was required for AR-mediated growth inhibition in ER+ and ER- breast cancer cells. We validated AR-GATA3 interaction and its transcriptional consequences in an ER+ patient-derived xenograft model that is growth inhibited by AR agonists. We also observed AR-GATA3 interactions in normal breast epithelial cells and co-localization of AR, GATA3, KDM4B and EHF expression in single cell RNA-seq breast tissue datasets.  In conclusion, AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in AR+ breast cancers regardless of ER status. This interaction facilitates the tumour suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumours and better overall survival in breast cancer. Our findings implicate AR-GATA3 interaction in normal breast biology, warranting investigation of AR activation for breast cancer prevention.

  1. Hickey, T.E. et al. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat Med 27, 310-320 (2021).
  2. Palmieri, C. et al. Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial. The Lancet Oncology 25, 317-325 (2024).
  3. Peters, A.A. et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res 69, 6131-40 (2009).
  4. Hosseinzadeh, L. et al. The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer. Genome Biol 25, 44 (2024)
  5. Hickey, T.E., Robinson, J.L., Carroll, J.S. & Tilley, W.D. Minireview: The androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol 26, 1252-67 (2012).