17-Hydroxyprogesterone/Progesterone Receptor B Signalling Disrupts the Metabolic Reprogramming in Breast Cancer Cell Lines

Introduction: Cancer cells rewire their metabolic networks to support growth and survival. Studies suggest the nuclear receptor involvement in breast cancer metabolic changes; however, the impact of progesterone receptor B (PR-B)/17-hydroxyprogesterone (OHPg) signaling on breast cancer metabolism has been underexplored. Materials and methods: Seahorse Analyzer was used to measure the oxygen consumption and acid efflux rate in OHPg treated breast cancer cells MCF7 and T47D. Enzymatic assays and western blotting analyses were performed to evaluate the activities and expression of main glycolysis and Tri carboxylic Acid Cycle (TCA) complexes. PR-B involvement was ascertained by using a specific PR-B siRNA. Results: Our results showed that in MCF7 and T47D cells, OHPg/PR-B signaling decreases glycolysis and ATP production, interfering on different cellular metabolic pathways. OHPg reduced pyruvate dehydrogenase expression and increased α-ketoglutarate dehydrogenase content, suggesting the induction of a ‘truncated’ TCA. Furthermore, in our cells OHPg augmented ATP citrate-lyase levels, but reduced the octanoyl-CoAdehydrogenase and fatty acid synthase activities, indicating a poor de novo lipid synthesis. Interestingly, lipase activity and fatty acid oxidation increased concomitantly to the triglyceride levels reduction. Conclusions: Collectively, OHPg/PR-B signaling perturbs breast cancer cell metabolism altering the metabolic reprogramming. OHPg can be used in combination with conventional chemotherapy to improve cancer treatment outcomes.