Constitutively active estrogen receptor- α (ER/ESR1) mutations have been identified in one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in directly promoting metastatic disease has not yet been mechanistically addressed in greater detail. In this talk, I will present data supporting the idea that ESR1 mutations play critical roles in a number of metastatic processes, in an allele- and context-dependent manner.
Anti-cancer drug treatments often do not completely eradicate all cancer cells in the body, leaving behind dormant cancer cells that can ultimately develop drug resistance to give rise to recurrent disease. ER+/HER2- breast cancer is a disease in which dormancy is highly relevant: roughly 1/3 of patients (~400,000 women every year worldwide) with early-stage disease treated with surgical resection and adjuvant endocrine therapy eventually experience disease recurrence. Recurrences of ER+ breast cancer occur over a long time frame (>20 years), suggesting that cancer cells can undergo prolonged periods of dormancy. Therapeutics that either maintain cancer cells in a dormant state or eradicate them would prevent cancer recurrence. We developed preclinical models of dormancy in ER+ breast cancer through estrogen deprivation, which occurs in patients treated with aromatase inhibitors as endocrine therapy. Such dormant breast cancer cells exhibit increased AMPK activation and mitochondrial respiration driven by fatty acid beta-oxidation. Pharmacological inhibition of beta-oxidation decreased dormant cancer cell burden in mice. However, pharmacological activation of AMPK or consumption of a high-fat diet blunted the anti-tumor effects of estrogen deprivation, leading to increased dormant BC cell burden. The metabolic features of dormant cancer cells may be exploited to develop improved treatments that would prevent disease recurrence.