Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer.

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to re-establish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.

内分泌治疗耐药是乳腺癌成功治疗的一个主要障碍。临床前和临床证据表明，乳腺癌细胞对抗雌激素药物的耐药与多种致癌酪氨酸激酶的过度表达和/或激活有关。夜班工作或紊乱的睡眠 - 觉醒周期对昼夜节律的干扰可能会增加患乳腺癌和其他疾病的风险。此外，夜间光照（LEN）会抑制褪黑素的夜间分泌，而褪黑素可抑制乳腺癌生长。在本研究中，我们使用雌激素受体α阳性（ERα +）的MCF - 7肿瘤异种移植大鼠模型来证明，通过微弱夜间光照（dLEN）改变光/暗周期如何加速乳腺肿瘤的发展，增加其代谢和生长，并使其对他莫昔芬治疗产生内在耐药性。在昼夜节律未被打乱的动物中，或者在接受微弱夜间光照（dLEN）但同时进行夜间褪黑素补充的动物中，不会出现这些特征。令人惊讶的是，我们的研究结果还表明，褪黑素既是一种肿瘤代谢抑制剂，也是一种受昼夜节律调节的激酶抑制剂，可重新建立乳腺肿瘤对他莫昔芬的敏感性并使肿瘤消退。总之，我们的研究结果表明，微弱夜间光照（dLEN）介导的夜间褪黑素分泌紊乱如何使肿瘤对他莫昔芬不敏感。