Abstract 3724: BMAL1 rewires mitochondrial metabolism and promotes tumor progress of triple negative breast cancer during insulin resistance

Abstract

Abstract Insulin resistance is a hallmark of metabolic diseases and negatively associated with breast cancer outcomes. While much work has dedicated to circadian dysregulation, metabolic diseases in breast cancer progression, the molecular mechanism connecting all these perspectives together has not yet established. To understand this underlying mechanism, we use in vitro and in vivo insulin-resistant triple-negative breast cancer (TNBC) models, illustrating that insulin resistance in TNBC reciprocally alters mitochondrial respiration and the expression of genes in the circadian rhythm pathway. Furthermore, genetic knockdown of BMAL1, an important circadian transcription factor, ablates key adaptations to insulin resistance, such as increased pyruvate flux, oxygen consumption, and lipid storage. Our in vivo study demonstrates that orthotopically transplanted E0771 mouse breast cancer cells with BMAL1 knocked down grow significantly faster than the parental counterpart in mice fed with the high-fat diet. This new understanding of BMAL1 expands our insights into circadian control of tumor metabolism and may lead to novel treatments for breast cancer. Citation Format: Cassandra A. Ramos, Ching Ouyang, Yue Qi, Yiyin Chung, Chun-Ting Cheng, Mark A. LaBarge, Victoria L. Seewasldt, David K. Ann. BMAL1 rewires mitochondrial metabolism and promotes tumor progress of triple negative breast cancer during insulin resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3724.