Endocrine Abstracts

In postmenopausal women, aromatase inhibitor (AI) therapy is the gold-standard first line treatment for ER-positive breast cancer. Unfortunately, many patients will suffer recurrence due to acquired AI resistance, creating an urgent need to elucidate the underlying mechanisms. Accumulating evidence shows that androgen/androgen receptor (AR) signaling is involved in AI resistance due to the androgenic environment dominating post-treatment. Exploration of the AR protein interactome via LC-MS/MS in AI resistant cells identified AR protein partners previously linked with castrate resistant prostate cancer, such as stress granule core component, G3BP1. Plant polyphenol (EGCG), an inhibitor of G3BP1 interaction, was used to explore the impact of stress granule (SG) complex inhibition across isogenic AI-sensitive and AI-resistant breast cancer cell lines utilising 3D bioprinted models of disease. Co-immunoprecipitation and confocal fluorescence imaging approaches were used to investigate the effect of EGCG and androgens (classical and 11-oxygenated) on G3BP1-AR protein complex formation. To date, our study has shown that androgen responsive AI resistant cells are exquisitely sensitive to disruption of SG formation. The interaction between extra-nuclear AR and G3BP1 is confirmed to be closely linked to cytoprotective mechanisms through its influence on SG formation, which is further modulated by the androgen/AR signaling pathway. Activation of the androgen/AR signaling pathway by both classical and 11-oxygenated adrenal androgens resulted in enhanced SG formation in AI-resistant LetR cells albeit through different mechanisms. In summary, exploration of the dynamic interplay between AR and G3BP1 will help us better understand the mechanisms of AI resistance in ER-positive breast cancer. Investigating the impact of AR protein and AR mRNA in SG regulation will help elucidate the complex and context dependent AI resistance mechanism regulated by androgen/AR in ER positive tumors. Further studies will focus on exploring the transcripts sequestered within SGs under exposure to various androgenic ligands.