Targeting androgen receptor and WNT pathway in endocrine-resistant mammary carcinomas with high AR and low ER and PR levels

Virginia Figueroa¹, Gabriela Pataccini¹, Martín C. Abba², Silvia Vanzulli³, Ana Sahores¹, Claudia Lanari¹, Caroline A. Lamb¹

Endocrine resistance remains a major drawback in the treatment of luminal breast cancer (BC). The mechanisms that contribute to hormone resistance may include deregulation of hormone receptors and growth factor signaling pathways. We previously demonstrated that overexpression of fibroblast growth factor (FGF2) in endocrine responsive T47D cell line, induced tumor progression. To explore the mechanisms underlying endocrine resistance we performed RNAseq analysis that revealed a deregulated WNT signaling pathway in T47D-FGF2-overexpressing cells compared with control T47D cells. We also detected decreased estrogen receptor α (ER) and progesterone receptor (PR) along with an increase in androgen receptor (AR) expression, both at mRNA and protein levels. Hence, FGF2-overexpressing cells have higher AR/ER and AR/PR ratios than control cells. Thus, we tested the effect of targeting the AR and/or WNT signaling pathways on cell proliferation and tumor growth. In endocrine resistant cells, dihydrotestosterone (DHT; AR agonist) induced cell proliferation while the combined treatment with enzalutamide (AR antagonist) and LGK974 (WNT inhibitor) inhibited tumor growth and reduced the number of large metastasis. Conversely, DHT inhibited control T47D cell proliferation and AR blockage had no significant effects on tumor growth. Our results suggest that targeting AR and/or WNT pathways may be a therapeutic alternative for endocrine resistant BC with high AR and low ER and PR levels.