摘要：SummaryThe 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 anin vitromodel 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.Graphical AbstractDisplay OmittedHighlights•Circadian regulator BMAL1 rewires metabolism in a chronic insulin-treated TNBC model•Pyruvate links BMAL1 to mitochondrial bioenergetics•BMAL1 suppresses tumor proliferation and metastasis in hyperinsulinemic obese mice•BMAL1 influences tumor microenvironment in high-fat-diet-fed miceBiological Sciences; Cell Biology; Chronobiology; Cancer
