Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal.

Chemotherapeutic resistance, particularly to doxorubicin (Dox), represents a major impediment to successfully treating breast cancer and is linked to elevated tumor metabolism and tumor over-expression and/or activation of various families of receptor- and non-receptor-associated tyrosine kinases. Disruption of circadian time structure and suppression of nocturnal melatonin production by dim light exposure at night (dLEN), as occurs with shift work, and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of an array of diseases, including breast cancer. Melatonin inhibits human breast cancer growth via mechanisms that include the suppression of tumor metabolism and inhibition of expression or phospho-activation of the receptor kinases AKT and ERK1/2 and various other kinases and transcription factors. We demonstrate in tissue-isolated estrogen receptor alpha-positive (ERα+) MCF-7 human breast cancer xenografts, grown in nude rats maintained on a light/dark cycle of LD 12:12 in which dLEN is present during the dark phase (suppressed endogenous nocturnal melatonin), a significant shortening of tumor latency-to-onset, increased tumor metabolism and growth, and complete intrinsic resistance to Dox therapy. Conversely, a LD 12:12dLEN environment incorporating nocturnal melatonin replacement resulted in significantly lengthened tumor latency-to-onset, tumor regression, suppression of nighttime tumor metabolism, and kinase and transcription factor phosphorylation, while Dox sensitivity was completely restored. Melatonin acts as both a tumor metabolic inhibitor and circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to Dox and drive tumor regression indicating that dLEN-induced circadian disruption of nocturnal melatonin production contributes to a complete loss of tumor sensitivity to Dox chemotherapy.

化疗耐药性，尤其是对阿霉素（Dox）的耐药性，是乳腺癌成功治疗的主要障碍，并且与肿瘤代谢升高以及各种受体相关和非受体相关酪氨酸激酶家族的肿瘤过度表达和/或激活有关。像轮班工作那样在夜间暴露于弱光（dLEN）导致的昼夜节律结构破坏和夜间褪黑素产生的抑制，以及/或者睡眠 - 觉醒周期紊乱，与包括乳腺癌在内的一系列疾病的风险显著增加有关。褪黑素通过包括抑制肿瘤代谢以及抑制受体激酶AKT和ERK1/2以及各种其他激酶和转录因子的表达或磷酸化激活等机制来抑制人类乳腺癌的生长。我们在组织分离的雌激素受体α阳性（ERα +）MCF - 7人乳腺癌异种移植物中证明，这些移植物在光/暗周期为LD 12:12且在暗期存在dLEN（内源性夜间褪黑素受抑制）的裸鼠中生长，肿瘤发病潜伏期显著缩短，肿瘤代谢和生长增加，并且对Dox治疗完全具有内在耐药性。相反，一个包含夜间褪黑素替代的LD 12:12无dLEN环境导致肿瘤发病潜伏期显著延长、肿瘤消退、夜间肿瘤代谢受抑制以及激酶和转录因子磷酸化受抑制，同时Dox敏感性完全恢复。褪黑素既是肿瘤代谢抑制剂又是昼夜节律调节的激酶抑制剂，可重新建立乳腺肿瘤对Dox的敏感性并促使肿瘤消退，这表明dLEN诱导的夜间褪黑素产生的昼夜节律紊乱导致肿瘤对Dox化疗的敏感性完全丧失。