Melatonin Supplementation in Complementary Breast Cancer Prevention

描述（由申请人提供）： 松果体激素褪黑激素是乳腺癌实验模型中肿瘤发生的有效抑制剂，而在人类中，较高和较低的夜间褪黑激素血液水平分别与较低和较高的乳腺癌风险相关。因此，拟议的转化研究项目的长期目标是对来自膳食补充剂的褪黑激素的作用有新的认识，作为预防人类乳腺癌生长的潜在新的补充医学策略。待测试的假设是，从膳食补充剂中摄取褪黑激素的人类女性将在其血液中具有一定水平的褪黑激素，当通过雌性裸大鼠中的人类乳腺癌异种移植物灌注时，其将在治疗和预防那些肿瘤的生长和代谢活性中发挥重要作用。这通过褪黑激素受体介导的机制发生，涉及抑制1）cAMP依赖性肿瘤亚油酸（LA）摄取，2）13-羟基十八碳二烯酸（13-HODE）形成，导致3）MEK/ERK 1/2和Akt/mTOR癌症生长/存活信号传导途径下调。我们的实验方法涉及一种新的模型系统，其中在雌性裸大鼠中生长的人乳腺癌异种移植物直接用从人类女性受试者中收集的全血原位灌注，所述全血在摄取膳食褪黑激素补充剂之前和之后。第一个目的是确定来源于膳食补充剂的褪黑激素对肿瘤增殖活性、LA摄取和13-HODE形成以及在组织分离的ER+和ER-MCF-7人乳腺癌异种移植物中的信号转导活性的剂量-反应效应，所述异种移植物在口服可商购的褪黑激素补充剂后用来自绝经前和绝经后女性志愿者的富含褪黑激素的全血原位直接灌注。第二个具体目的是测试特定褪黑激素受体阻断剂对来自口服褪黑激素补充剂后的人类志愿者的富含褪黑激素的全血在原位灌注期间抑制ER+和ER-人乳腺癌异种移植物中的肿瘤增殖活性和LA摄取和代谢以及信号转导活性的能力的影响。在这两个目标中，将确定来自膳食补充剂的褪黑激素对肿瘤cAMP水平和MEK/ERK 1/2和Akt/mTOR增殖/存活信号传导途径的激活的影响。从这种创新的转化方法中获得的知识将为第一次大规模临床乳腺癌治疗和/或预防试验的设计提供合理的生物学基础，该试验使用市售褪黑激素补充剂作为新的补充医疗策略。公共卫生相关性：最近发现，上夜班的妇女患乳腺癌的风险显著增加，加上公众认识的提高和非处方褪黑激素补充剂的广泛使用，使得褪黑激素补充剂成为乳腺癌风险、预防和治疗方面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第一个补充褪黑激素用于乳腺癌治疗和预防的临床试验提供关键的一步，特别是在高危人群中，如夜班工人。

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.