Melatonin: an inhibitor of breast cancer.
Melatonin: an inhibitor of breast cancer.
复制标题
DOI：
10.1530/erc-15-0030
复制
发表时间：
2015-06
影响因子：
3.9
通讯作者：
Blask DE
中科院分区：
文献类型：
--
作者：
Hill SM;Belancio VP;Dauchy RT;Xiang S;Brimer S;Mao L;Hauch A;Lundberg PW;Summers W;Yuan L;Frasch T;Blask DE
这篇综述讨论了褪黑素介导的昼夜节律调节以及参与人类乳腺癌生长的代谢和分子信号传导机制的最新研究，以及夜间暴露在光线 (LEN) 造成的昼夜节律破坏的相关后果。昼夜节律褪黑激素信号在人乳腺癌细胞系和异种移植物中的抗癌作用很大程度上涉及 MT1 受体介导的机制。在雌激素受体 α (ERα) 阳性的人乳腺癌中，褪黑激素通过 MT1 受体抑制 ERα mRNA 表达和 ERα 转录活性。此外，褪黑激素还调节核受体超家族其他成员的反式激活、雌激素代谢酶以及核心时钟和时钟相关基因的表达。此外，褪黑激素还抑制肿瘤有氧代谢（瓦伯格效应），进而抑制对细胞增殖、细胞存活、转移和耐药性至关重要的细胞信号传导途径。褪黑素在乳腺癌细胞中表现出细胞抑制和细胞毒活性，并且似乎具有细胞类型特异性。褪黑激素还具有抗侵袭/抗转移作用，涉及多种途径，包括抑制 p38 MAPK 和抑制上皮间质转化。研究表明，褪黑激素通过抑制 LINE-1 逆转录转座子的表达来促进基因组稳定性。最后，动物和人类模型研究表明，LEN 诱导的昼夜节律夜间褪黑激素信号破坏可促进人类乳腺癌的生长、代谢和信号传导，从而驱动乳腺肿瘤产生内分泌和化疗耐药性。这些数据为夜班工人和其他越来越多地暴露于 LEN 的个人中乳腺癌风险升高的流行病学证据提供了最有力的理解和支持。
This review discusses recent work on melatonin-mediated circadian regulation and metabolic and molecular signaling mechanisms involved in human breast cancer growth and associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin, via the MT1 receptor, suppresses ERα mRNA expression and ERα transcriptional activity. As well, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (Warburg effect), and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways including inhibition of p38 MAPK and repression of epithelial-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models indicate that LEN induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer to drive breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms underpinning the epidemiologic demonstration of elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN.