Abstract 796: Progestins target mitochondrial respiration to shift metabolic phenotype in luminal breast cancer

Abstract

Abstract The dichotomous nature of progesterone receptor (PR) in estrogen receptor (ER)-positive breast cancers has confounded its use as an endocrine target. Historically, progestins were used to treat some advanced breast cancers and ongoing clinical trials are testing several PR ligands. PR generally opposes ER activity through multiple mechanisms, most notably by altering global ER transcriptional activity to suppress breast tumor growth. However, progestins can also stimulate expansion of endocrine-resistant cancer stem cells (CSCs). Thus, better understanding of potential consequences of progestins in breast cancer is necessary to gauge therapeutic efficacy. Given that ER-driven tumor growth relies on mitochondrial respiration, we evaluated whether PR modulates cell metabolism machinery as a mechanism of ER antagonism. We used functional and morphometric assays in an ER+ breast cancer cell line and patient-derived tumor models to show that progestin treatment dramatically alters mitochondrial function. Multivariate metabolomics analysis highlights a progestin-associated metabolic signature involving accumulation of multiple TCA cycle intermediates, including fumarate, malate, and succinate. Functional assays indicate that progestins impair mitochondrial oxidative reserve capacity and oxygen consumption while ablating estradiol-induced accumulation of ATP in PR+ but not PR− cells. Morphometric assessment of mitochondria via laser-scanning confocal and transmission electron microscopy indicate a shift away from reticular filamentous mitochondria towards smaller, rounder, more perinuclear mitochondria with altered membrane potential. These results suggest that PR targets mitochondrial respiration as part of a broader strategic shift from ER-driven tumor growth to PR-driven thrifty metabolic dormancy. Whether the latter is indicative of an acquired propensity for glycolytic metabolism in indolent tumor cells, CSCs, or perhaps both, is addressed in ongoing studies. Citation Format: Shawna B. Matthews, Lynsey M. Fettig, Ashley V. Ward, Matthew R. Jackman, Paul S. MacLean, Carol A. Sartorius. Progestins target mitochondrial respiration to shift metabolic phenotype in luminal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 796.