Abstract Glucocorticoids promote metabolic reprogramming associated with enhanced proliferation of rat mammary gland cancer cells Exposure to chronic stressors can have a significant role in both disrupting normal mammary gland development as well as potentially negatively impacting the breast cancer outcome. Glucocorticoids (GCs) are stress responsive steroid hormones that mediate cellular and physiological stress responses via activating the GC receptor (GR). While several studies have sought to understand how prolonged physiological GC exposure and GR stimulation negatively impact mammary gland health and breast cancer outcomes, much work remains to be done. We used the rat mammary gland (MG) adenocarcinoma LA7 cell line, a rat MG cancer cell line derived in vitro from an in vivo DMBA carcinogen-induced mammary tumor; to begin to uncover how chronic stress hormones might affect metabolism and energy production in MG epithelial cancer as well as elucidate the molecular mechanisms underlying these effects. LA7 cells were treated either with or without 140nM (high physiological level) of the rat GC corticosterone for 0-72 hours to mimic acute to chronic stress exposure. RNA-Seq results from the LA7 cells demonstrated that under conditions of corticosterone-induced GR stimulation there was a significant increase in expression of mitochondrial-encoded genes such as MT-ND1, MT-CO1, and MT-ATP6, suggesting an unexpected rise in mitochondrial biogenesis. In addition, several nuclear genes encoding proteins involved in mitochondrial metabolism including Isocitrate Dehydrogenase and Succinate Dehydrogenase were also upregulated. We then asked whether these metabolic gene expression changes accompanied expected cell phenotypic changes. MitoTracker Green and Red staining was used to measure mitochondrial number/mass and mitochondrial membrane potential (MMP), respectively. These experiments confirmed that both mitochondrial number/mass and MMP was significantly upregulated by chronic GR activation with GC exposure. In agreement with the MMP staining data, intracellular ATP abundance was shown to be significantly upregulated by chronic GR activation. Using a Seahorse XF Mito-Stress test we observed metabolic reprogramming showing that chronic GR activation promoted significant elevation in basal, ATP-linked, and spare capacity respiration/oxidative phosphorylation (OXPHOS). Because OXPHOS activity is integrally linked to the process of glucose metabolism, we sought to determine if chronic GR activation in the LA7 cells impacts glycolysis. To do this we performed a Seahorse XF Glycolysis Stress test, as well as measured glucose uptake and lactate secretion. The Seahorse XF Glycolysis Stress test revealed an increase in basal glycolysis and glycolytic capacity in the LA7 cells. In parallel, both glucose uptake and lactate production and secretion were also elevated. Lastly, a cellular proliferation assay showed increased cell division following chronic stress hormone exposure. Overall, these observations suggest that in addition to upregulating mitochondrial biogenesis, OXPHOS, and glycolytic activity, corticosterone can contribute to rat MG cancer cellular proliferation. These data also suggest that chronic stress exposure and the resulting GC exposure leads to increased overall cellular metabolism and energy production and promotes a shift to a highly energetic and more proliferative phenotype in a model of mammary cancer. Citation Format: J. Dowgielewicz, J. Caraveo, B. Faubert, M. McClintock, S. Conzen, M. Brady. Glucocorticoids promote metabolic reprogramming that underlies enhanced proliferation of breast cancer stem and progenitor cells under conditions of chronic stress abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-13-04.
Dowgielewicz et al. (Tue,) studied this question.
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