Abstract
Progesterone receptors (PR) profoundly influence breast cancer biology by modifying estrogen receptor (ER) gene regulation, and, under some contexts, increasing populations of cancer stem cells. Abnormal metabolism is a cancer hallmark that has largely been understudied in relation to hormones in ER+PR+ breast disease. In this study, we investigated how progestins, in the absence or presence of estrogens, affect breast cancer cell metabolism. We measured metabolites using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) in three ER+PR+ breast cancer cell lines (T47D, UCD4, and UCD65) treated with vehicle, estrogen only, progestin only, or the combination. Progestins, in the absence or presence of estrogens, largely downregulated metabolites, particularly those involved in tricarboxylic acid (TCA) cycle and amino acid metabolism. Seahorse metabolic analysis found progestins (alone or plus estrogens) generally shifted cells towards glycolysis with reduced ATP production. Transmission electron microscopy in cell lines and patient-derived xenograft tumors found that estrogens produced an elongated mitochondrial morphology, while estrogen plus progestin treatment reversed this trend. Using the photoconvertible MitoTimer reporter, progestins reduced both baseline and estrogen-induced mitochondrial turnover. Progestins blocked the estrogen-induced expression of mitochondrial biogenesis regulators PGC1α and PGC1β and their downstream targets. These findings indicate that progestins dominantly affect cell metabolism to shift cells to a more glycolytic phenotype with reduced mitochondrial function and amino acid pools; this transition is indicative of less proliferative, but also more dedifferentiated cells. Our results highlight potential benefits and detriments of current clinical studies testing selective PR modulators in ER+ breast cancers.
Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility