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• W4308138251 abstract "Abstract Estrogen receptor positive (ER+) breast cancer is the most common subtype among all breast cancers and is responsible for most breast cancer related deaths. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but the majority of advanced ER+ breast cancers eventually become refractory to endocrine therapies. Therefore, understanding the underlying molecular mechanisms that enable or promote resistance to endocrine therapies may lead to novel therapeutic targets.Cancer cells have a high energy demand and as a result consume greater quantities of glucose to meet their energy and anabolic demands to support cell growth and proliferation. In this study, we used breast cancer cell models that are endocrine therapy sensitive and resistant and investigated the metabolic flux of glucose by growing the cells in the presence of the stable glucose isotope, UC13-Glucose. We measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. Notably, in LCC9 cells the m+4 and m+6 isotopomer of C-13 labelled citrate was absent. Further, in LCC9 cells, C-13 labelled fumarate was very low while the succinate: fumarate ratio was markedly higher. These results suggest that the TCA cycle is impaired in LCC9 cells and the conversion of succinate to fumarate is dysregulated. Succinate dehydrogenase (SDH) enzyme is responsible for catalytic conversion of succinate to fumarate. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Our study further showed that SDHAF2 protein was under expressed in LCC9 cells compared with LCC1 cells, likely contributing to lower SDH activity. Intriguingly, when SDH activity was inhibited using dimethylmalonate, the LCC9 were re-sensitized to both Fulvestrant and 4-hydroxytamoxifen. Data analysis of clinical samples shows that poor relapse free survival in ER+ breast cancer patients is correlated with lower expression levels of SDHAF2. Overall, this study suggests that targeting succinate metabolism may help to restore sensitivity to Fulvestrant and tamoxifen in endocrine therapy resistance in ER+ breast cancer cells. Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m." @default.
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• W4308138251 date "2022-11-01" @default.
• W4308138251 modified "2023-09-30" @default.
• W4308138251 title "OR30-2 Targeting Succinate Metabolism in Endocrine Therapy Resistant, ER Positive, Breast Cancer Cells" @default.
• W4308138251 doi "https://doi.org/10.1210/jendso/bvac150.1825" @default.
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