Melatonin Supplementation in Complementary Breast Cancer Prevention

补充褪黑激素可辅助预防乳腺癌

• 批准号: 8115976
• 负责人: DAVID BLASK
• 金额: $ 16.26万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-10 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115976
• 关键词: 13-hydroxyoctadecadienoic acid; Address; Awareness; Biological; Biological Models; Blood; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Prevention Trial; Breast Cancer Treatment; Clinical; Clinical Trials; Cyclic AMP; Dose; Down-Regulation; Experimental Models; Female; Future; Growth; Health; Hormones; Human; Human Activities; Human Volunteers; In Situ; Ingestion; Intake; Knowledge; Linoleic Acids; MAPK3 gene; MCF7 cell; MEKs; Malignant Neoplasms; Mediating; Medical; Melatonin; Melatonin Receptors; Metabolic; Metabolism; Nude Rats; Oral; Perfusion; Physiological; Pineal gland; Play; Population; Postmenopause; Premenopause; Prevention; Public Health; Receptor, Melatonin, MT2; Research; Research Project Grants; Risk; Role; Signal Pathway; Signal Transduction; Supplementation; Testing; Tissues; Translational Research; Whole Blood; Woman; Work; Xenograft procedure; base; cancer prevention; cancer risk; design; dietary supplements; dosage; high risk; human FRAP1 protein; human female; inhibitor/antagonist; innovation; malignant breast neoplasm; novel; prevent; response; shift work; translational approach; tumor; tumorigenesis; uptake; volunteer

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.

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，夜间褪黑激素血液水平分别与较低和更高的乳腺癌风险有关。因此，拟议的翻译研究项目的长期目标是对褪色补充剂的作用有了新的了解，作为防止人类乳腺癌生长的潜在互补医学策略。要检验的假设是，从饮食补充剂中摄入褪黑激素的人类女性将在其血液中具有水平的褪黑激素水平，而当通过人类乳腺癌的乳腺癌异种移植物中灌注时，在女性裸鼠中，将在这些肿瘤的生长和代谢活性的治疗和预防中起重要作用。这是通过褪黑激素受体介导的机制发生的，涉及抑制1）cAMP依赖性肿瘤亚油酸（LA）摄取，2）13-羟基二十二烯酸（13-氢）的形成，导致3）MEK/ERK1/2和AKT/MTOR癌症的增长/MEK1/MTOR癌症的增长/Simble fortage fortage。我们的实验方法涉及一种新型的模型系统，其中人类乳腺癌的异种移植物生长在女性裸鼠中，直接灌注原位，在摄入饮食中的褪黑激素补充剂摄入之前和之后，从人类女性受试者中收集了全血。第一个目的是确定从饮食补充剂中得出的褪黑激素对肿瘤增殖活性，LA摄取和13次体的形成以及组织分离的ER+和ER-MCF-7人类乳腺癌的信号转导活性的剂量反应影响，以及信号转导活性，直接促进梅拉托蛋白富含绿色蛋白质的血液和后，并且是富含梅拉托蛋白的妇女效率的，并且是一位富含梅拉托蛋白的富含剂量的含量，并且褪黑激素补充。第二个具体目的是测试特定的褪黑激素受体阻滞剂对褪黑激素富含血液的能力的影响，从口腔摄入褪黑激素补充剂后的人类志愿者，抑制肿瘤增殖活性以及La uptake和la uttake and Nemake和代谢，以及在Site Incue in Cerfusion in Cerfusion in ER+和eR型乳腺癌Xenograft中的信号转导活性。在这两个目的中，将在饮食补充剂中的褪黑激素的作用在肿瘤营地水平以及MEK/ERK1/2和Akt/MTOR增殖/存活信号通路的激活上确定。从这种创新的，转化方法获得的知识将为设计首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，以市售褪黑激素的补充作为一种新的补充医疗策略。公共卫生相关性：最近识别夜间工作的女性乳腺癌风险大大增加，以及公众意识提高并广泛使用非处方褪黑激素补充剂，这使褪黑激素补充剂是乳腺癌风险，预防和治疗中重要的公共健康问题。从我们的新型研究方法中获得的信息将为未来设计褪黑激素治疗的临床试验的未来设计提供至关重要的步骤，尤其是在诸如夜班工人之类的高风险人群中。

项目成果

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

夜间暴露在光线下造成的昼夜节律和褪黑激素的破坏会导致乳腺癌对他莫昔芬治疗产生内在耐药性。

• DOI: 10.1158/0008-5472.can-13-3156
• 发表时间: 2014-08-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Dauchy RT;Xiang S;Mao L;Brimer S;Wren MA;Yuan L;Anbalagan M;Hauch A;Frasch T;Rowan BG;Blask DE;Hill SM
• 通讯作者: Hill SM

Melatonin: an inhibitor of breast cancer.

• DOI: 10.1530/erc-15-0030
• 发表时间: 2015-06
• 期刊: Endocrine-related cancer
• 影响因子: 3.9
• 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
• 通讯作者: Blask DE

A Method for Growing Tissue-Isolated Human Tumor Xenografts in Nude Rats for Melatonin/Cancer Studies.

一种在裸鼠中培养组织分离的人类肿瘤异种移植物用于褪黑激素/癌症研究的方法。

• DOI: 10.1007/978-1-0716-2593-4_47
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Dauchy,RobertT;Hill,StevenM;Blask,DavidE
• 通讯作者: Blask,DavidE

Breast cancer and circadian disruption from electric lighting in the modern world.

• DOI: 10.3322/caac.21218
• 发表时间: 2014-05
• 期刊: CA: a cancer journal for clinicians
• 作者: Stevens RG;Brainard GC;Blask DE;Lockley SW;Motta ME
• 通讯作者: Motta ME

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

• DOI: 10.1111/jpi.12239
• 发表时间: 2015-08
• 期刊: Journal of pineal research
• 影响因子: 10.3
• 作者: Xiang S;Dauchy RT;Hauch A;Mao L;Yuan L;Wren MA;Belancio VP;Mondal D;Frasch T;Blask DE;Hill SM
• 通讯作者: Hill SM