A Non-canonical Function of BMAL1 Metabolically Limits Obesity-Promoted Triple-Negative Breast Cancer

Cassandra A Ramos; Ching Ouyang; Yue Qi; Yiyin Chung; Chun-Ting Cheng; Mark A LaBarge; Victoria L Seewaldt; David K Ann

doi:10.1016/j.isci.2020.100839

A Non-canonical Function of BMAL1 Metabolically Limits Obesity-Promoted Triple-Negative Breast Cancer

iScience. 2020 Feb 21;23(2):100839. doi: 10.1016/j.isci.2020.100839. Epub 2020 Jan 14.

Authors

Cassandra A Ramos¹, Ching Ouyang², Yue Qi³, Yiyin Chung³, Chun-Ting Cheng³, Mark A LaBarge⁴, Victoria L Seewaldt⁴, David K Ann⁵

Affiliations

¹ Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.
² Center for Informatics, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
³ Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁴ Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA; Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁵ Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA. Electronic address: dann@coh.org.

Abstract

The epidemiological association between disrupted circadian rhythms and metabolic diseases is implicated in increased risk of human breast cancer and poor therapeutic outcomes. To define a metabolic phenotype and the underlying molecular mechanism, we applied chronic insulin treatment (CIT) to an in vitro model of triple-negative breast cancer to directly address how BMAL1, a key circadian transcription factor, regulates cancer cell respiration and governs tumor progression. At the cellular level, BMAL1 suppresses the flexibility of mitochondrial substrate usage and the pyruvate-dependent mitochondrial respiration induced by CIT. We established an animal model of diet-induced obesity/hyperinsulinemia and observed that BMAL1 functions as a tumor suppressor in obese, but not lean, mice. Downregulation of BMAL1 is associated with higher risk of metastasis in human breast tumors. In summary, loss of BMAL1 in tumors confers advantages to cancer cells in both intrinsic mitochondrial metabolism and extrinsic inflammatory tumor microenvironment during pre-diabetic obesity/hyperinsulinemia.

Keywords: Biological Sciences; Cancer; Cell Biology; Chronobiology.

Abstract

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