Background: Breast cancer is the most common newly diagnosed malignancy worldwide, affecting millions of women annually. Breast cancer is also a leading cause of cancer-related mortality, with an estimated 3,000 deaths in 2020 in Australia. The oncogenic role of the estrogen receptor (ER) in the luminal sub-types of breast cancer (75-80% of all cases) is well described. The androgen receptor (AR) is expressed more frequently than ER in breast cancer. Almost all ER+ cases and approximately half of ER- cases express AR, leading to recent interest as a potential therapeutic target. However, the role of AR in breast cancer is complex, with studies indicating context-specific tumour suppressor (luminal) and oncogenic (molecular apocrine) activities. To better understand the functional role of AR in breast cancer, we undertook proteomic studies to identify AR interacting proteins in both ER+ and ER- breast cancer contexts.
Results: We identified GATA3 as a novel AR interacting protein in breast cancer in vitro models regardless of ER status. This interaction was confirmed in clinical specimens of normal and malignant breast epithelia. Androgen stimulation of breast cancer cells induced nuclear translocation of AR and GATA3, and ChIP-seq analysis revealed enrichment of overlapping AR and GATA3 chromatin binding events. Using cell line and patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of androgen-induced AR and GATA3 cis-regulatory elements across both ER+ and ER- models. Knockdown experiments indicated that GATA3 acts as an AR co-regulatory factor to upregulate the transcription of known luminal-lineage genes (e.g. KRT19, EHF, AQP3, and CLDN7) and downregulate basal-lineage genes (e.g. TP63, SMAD3, and ELK3).
Conclusions: Our findings indicate that AR and GATA3 interact in breast epithelial cells to drive the expression of luminal lineage markers and provide a mechanism underpinning breast cancers that are classified as having a luminal transcriptome irrespective of ER status.