Abstract 1627: Metabolic links between obesity and ferroptosis in a murine model of breast cancer

Abstract Background Obesity is an established risk factor for post-menopausal triple negative breast cancer (TNBC). Multiple aspects of fatty acid metabolism, including fatty acid synthesis, are upregulated in white adipose tissue during obesity development. The enzyme pyruvate carboxylase (PC), a supportive player in fatty acid synthesis, is relied upon for metastasis of murine TNBC particularly in models of obesity- further elucidating the importance of fatty acid metabolism to breast cancer progression in those with obesity. Ferroptosis, a method of cell death induced by peroxidation of phospholipid fatty acyl chains, is a recently discovered and rapidly developing mechanistic target in multiple cancer types. While several cancers, including breast cancer, are sensitive to ferroptosis induced by different mechanisms, the metabolic vulnerabilities and consequent therapeutic potential of ferroptosis are just beginning to be explored. This study aims to determine whether obesity-driven reprogramming of fatty acid metabolism exacerbates breast cancer progression via altered sensitivity to ferroptosis Methods The relationship between obesity, breast cancer and lipid peroxidation was investigated in vitro via proliferation assays, qPCR, Western blot and flow cytometry using multiple murine models of breast cancer treated with erastin and RSL3. PC was suppressed using shRNA introduced via lentiviral transduction. In vivo tumor growth in lean and obese mice was determined following treatment with erastin, RSL3, or a vehicle control. Results In vitro data reveals that TNBC cells are highly sensitive to treatment with the ferroptosis-inducing molecules erastin and RSL3. Erastin treatment transcriptionally induces PC expression in several murine models of TNBC in vitro. Suppression of PC at baseline (without ferroptosis induction) is sufficient to induce transcription of glutathione peroxidase-4 (a critical regulator of ferroptosis). While Affymetrix array data of untreated metastatic M-WntLung primary tumors showed a decrease in PC and associated genes in tumors from obese mice relative to lean mice, treatment with erastin increased PC expression specifically in tumors from obese mice. Tumors from obese mice relative to control mice have an altered response to treatment with the ferroptosis inducing molecules erastin and RSL3. Conclusion These data indicate that obesity-associated dysregulation of lipid metabolism and regulation of PC may be key determinants of sensitivity to induction of ferroptosis. Future work will delineate the relationship between breast cancer, ferroptosis, and fatty acid metabolism utilizing in vivo models to determine whether ferroptosis-specific mechanisms are exacerbated with PC suppression to further impede obesity-exacerbated tumor growth. Citation Format: Emily Devericks, Michael F. Coleman, Hannah Malian, Violet Kiesel, Dorothy Teegarden, Stephen D. Hursting. Metabolic links between obesity and ferroptosis in a murine model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1627.