17-β Estradiol up-regulates energy metabolic pathways, cellular proliferation and tumor invasiveness in ER+ breast cancer spheroids

• Published in: Frontiers in oncology 2022-11, Vol.12, p.1018137
• Main Authors: Pacheco-Velázquez, Silvia Cecilia, Ortega-Mejía, Ingrid Itzayanna, Vargas-Navarro, Jorge Luis, Padilla-Flores, Joaquín Alberto, Robledo-Cadena, Diana Xochiquetzal, Tapia-Martínez, Gabriela, Peñalosa-Castro, Ignacio, Aguilar-Ponce, José Luis, Granados-Rivas, Juan Carlos, Moreno-Sánchez, Rafael, Rodríguez-Enríquez, Sara
• Format: Article
• Language: English
• Subjects: 17-β estradiol; anti-mitochondrial therapy; ER+ breast cancer; glycolysis; metastasis; Oncology; OxPhos
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.1018137

Several biological processes related to cancer malignancy are regulated by 17-β estradiol (E2) in ER+-breast cancer. To establish the role of E2 on the atypical cancer energy metabolism, a systematic study analyzing transcription factors, proteins, and fluxes associated with energy metabolism was undertaken in multicellular tumor spheroids (MCTS) from human ER+ MCF-7 breast cancer cells. At E2 physiological concentrations (10 and 100 nM for 24 h), both ERα and ERβ receptors, and their protein target pS2, increased by 0.6-3.5 times . non-treated MCTS, revealing an activated E2/ER axis. E2 also increased by 30-470% the content of several transcription factors associated to mitochondrial biogenesis and oxidative phosphorylation (OxPhos) (p53, PGC1-α) and glycolytic pathways (HIF1-α, c-MYC). Several OxPhos and glycolytic proteins (36-257%) as well as pathway fluxes (48-156%) significantly increased being OxPhos the principal ATP cellular supplier (>75%). As result of energy metabolism stimulation by E2, cancer cell migration and invasion processes and related proteins (SNAIL, FN, MM-9) contents augmented by 24-189% non-treated MCTS. Celecoxib at 10 nM blocked OxPhos (60%) as well as MCTS growth, cell migration and invasiveness (>40%); whereas the glycolytic inhibitor iodoacetate (0.5 µM) and doxorubicin (70 nM) were innocuous. Our results show for the first time using a more physiological tridimensional cancer model, resembling the initial stages of solid tumors, that anti-mitochondrial therapy may be useful to deter hormone-dependent breast carcinomas.