Androgen Receptors Promote Oxidative Phosphorylation and Resistance to Palmitate Lipotoxicity in ER-Mutant Breast Cancer

Aromatase inhibitors (AI) are first-line therapy for postmenopausal women with estrogen receptor-expressing (ER+) breast Cancer (BC). AI therapy effectively reduces recurrence and extends lifespan for patients with ER+ BC through long-term estrogen deprivation (LTED) resulting from inhibition of the enzyme aromatase that converts androgens to estrogens. However, up to 50% of ER+ BC recurs as AI-resistant metastatic disease within 10 years of diagnosis. AI-resistant BC upregulates androgen receptors (AR) and mitochondrial Oxidative Phosphorylation (OXPHOS) and requires OXPHOS and fatty acid oxidation (FAO). The liver and lung, common ER+ BC metastatic sites, have high abundance of the saturated fatty acid palmitate. We asked whether AR signaling regulates OXPHOS in the context of LTED. Using mutant ER-expressing MCF7 and T47D BC cell lines with AR antagonism via the anti-androgen enzalutamide and with shRNA knockdown, we demonstrate that AR supports cell growth, OXPHOS, FAO, and resistance to palmitate lipotoxicity. We identify AR as a positive regulator of the carnitine Acyltransferase family enzyme CRAT that promotes OXPHOS capacity. These studies identify AR as pro-tumor in the LTED setting and as a therapeutic target for ER-mutant BC that develops under the selective pressure of AI therapy.

androgen receptor; breast cancer; estrogen receptor; fatty acid oxidation; mitochondria; oxidative phosphorylation.