Melatonin Supplementation in Complementary Breast Cancer Prevention

描述(由申请人提供)： 在乳腺癌的实验模型中，松果体激素褪黑素是一种有效的肿瘤发生抑制因子，而在人类中，夜间血液中较高和较低的褪黑素水平分别与较低和较高的乳腺癌风险相关。因此，拟议的转译研究项目的长期目标是对来自膳食补充剂的褪黑素的作用有一个新的理解，作为预防人类乳腺癌生长的潜在新的补充医学策略。要测试的假设是，从膳食补充剂中摄取褪黑素的人类女性血液中的褪黑素水平，当通过女性裸鼠的人乳腺癌移植瘤灌流时，将在治疗和防止这些肿瘤的生长和代谢活动方面发挥重要作用。这是通过褪黑素受体介导的机制实现的，该机制涉及1)cAMP依赖的肿瘤亚油酸(LA)摄取，2)13-羟基十八碳二烯酸(13-HODE)的形成，导致3)MEK/ERK1/2和Akt/mTOR癌症生长/生存信号通路的下调。我们的实验方法涉及一种新的模型系统，在该模型系统中，在雌性裸鼠体内生长的人乳腺癌移植瘤直接与从人类女性受试者采集的全血直接原位灌流，在摄入褪黑激素补充剂之前和之后。第一个目的是确定来自膳食补充剂的褪黑素对肿瘤增殖活性、LA摄取和13-HODE形成以及信号转导活性的剂量-反应效应。第二个具体目的是测试一种特定的褪黑素受体阻滞剂对口服褪黑素补充剂后人类志愿者富含褪黑素的全血在原位灌流过程中抑制ER和ER-人乳腺癌移植瘤的肿瘤增殖活性、LA摄取和代谢以及信号转导活性的影响。在这两个目标中，来自膳食补充剂的褪黑素对肿瘤cAMP水平以及MEK/ERK1/2和Akt/mTOR增殖/生存信号通路的激活的影响将被确定。从这种创新的转化方法中获得的知识将为设计第一个大规模临床乳腺癌治疗和/或预防试验提供合理的生物学基础，该试验使用商业上可用的褪黑素补充剂作为一种新的补充医学策略。与公共健康相关：最近发现，上夜班的女性患乳腺癌的风险显著增加，再加上公众意识的提高和非处方药褪黑素补充剂的广泛使用，使褪黑素补充剂成为乳腺癌风险、预防和治疗中的一个重要公共卫生问题。从我们新的研究方法中获得的信息将为未来设计褪黑素补充用于乳腺癌治疗和预防的第一个临床试验提供关键步骤，特别是在夜班工人等高危人群中。

DESCRIPTION (provided by applicant): The pineal gland hormone melatonin is a potent inhibitor of tumorigenesis in experimental models of breast cancer while, in humans higher and lower nocturnal melatonin blood levels are associated with lower and higher breast cancer risk, respectively. Therefore, the long-term objective of the proposed translational research project is to gain a new understanding of the role of melatonin, derived from dietary supplements, as a potentially new complementary medical strategy for preventing the growth of human breast cancer. The hypothesis to be tested is that human females who have ingested melatonin from dietary supplements will have levels of melatonin in their blood which, when perfused through human breast cancer xenografts in female nude rats, will play a significant role in the treatment and prevention of the growth and metabolic activity of those tumors. This occurs through a melatonin receptor-mediated mechanism involving the suppression of 1) cAMP-dependent tumor linoleic acid (LA) uptake, 2) 13-hydroxyoctadecadienoic acid (13-HODE) formation, leading to a down-regulation of the 3) MEK/ERK1/2 and Akt/mTOR cancer growth/survival signaling pathways. Our experimental approach involves a novel model system in which human breast cancer xenografts, growing in female nude rats, are directly perfused in situ with whole blood collected from human female subjects prior to and following the ingestion of a dietary melatonin supplement. The first aim is to determine the dose-response effects of melatonin derived from dietary supplements on tumor proliferative activity, LA uptake and 13-HODE formation, and signal transduction activity in tissue- isolated ER+ and ER- MCF-7 human breast cancer xenografts directly perfused in situ with melatonin-rich whole blood from pre- and postmenopausal female volunteers following the oral intake of a commercially available melatonin supplement. The second specific aim is to test the effects of a specific melatonin receptor blocker on the ability of melatonin-rich whole blood, from human volunteers following the oral intake of a melatonin supplement, to suppress tumor proliferative activity and LA uptake and metabolism, and signal transduction activity in ER+ and ER- human breast cancer xenografts during perfusion in situ. In both aims, the effects of melatonin from dietary supplements will be determined on tumor cAMP levels and the activation of the MEK/ERK1/2 and Akt/mTOR proliferation/survival signaling pathways. The knowledge obtained from this innovative, translational approach will provide a rational biological basis for the design of the first large-scale clinical breast cancer treatment and/or prevention trials using commercially available melatonin supplementation as a new complementary medical strategy. PUBLIC HEALTH RELEVANCE: The recent identification of a significantly increased risk of breast cancer in women who work night shifts together with increased public awareness and widespread use of over-the-counter melatonin supplements, makes melatonin supplementation an important public health issue in breast cancer risk, prevention and treatment. The information gained from our novel research approach will provide a critical step for the future design of the first clinical trial of melatonin supplementation for breast cancer treatment and prevention particularly in high risk populations such as night shift workers.