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）： 在乳腺癌实验模型中，松果体激素褪黑激素是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源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补充医学策略。待测试的假设是，从膳食补充剂中摄入褪黑激素的人类女性，其血液中的褪黑激素水平会升高，当通过雌性裸鼠的人类乳腺癌异种移植物进行灌注时，将在治疗和预防乳腺癌方面发挥重要作用。这些肿瘤的生长和代谢活动。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-羟基十八碳二烯酸 (13-HODE) 形成，导致 3) MEK 下调/ERK1/2 和 Akt/mTOR 癌症生长/生存信号通路。我们的实验方法涉及一种新颖的模型系统，其中在雌性裸鼠中生长的人类乳腺癌异种移植物在摄入膳食褪黑激素补充剂之前和之后直接原位灌注从人类女性受试者收集的全血。第一个目的是直接确定膳食补充剂中褪黑激素对组织分离的 ER+ 和 ER- MCF-7 人乳腺癌异种移植物中肿瘤增殖活性、LA 摄取和 13-HODE 形成以及信号转导活性的剂量反应影响在口服市售褪黑激素补充剂后，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进行原位灌注。第二个具体目标是测试特定褪黑激素受体阻滞剂对口服褪黑激素补充剂后的人类志愿者富含褪黑激素的全血的影响，以抑制肿瘤增殖活性和 LA 摄取和代谢，并发出信号原位灌注期间 ER+ 和 ER- 人乳腺癌异种移植物中的转导活性。在这两个目标中，膳食补充剂中褪黑激素的作用将取决于肿瘤 cAMP 水平以及 MEK/ERK1/2 和 Akt/mTOR 增殖/生存信号通路的激活。从这种创新的转化方法中获得的知识将为设计第一个使用市售褪黑激素补充剂作为新的补充医疗策略的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。公共健康相关性：最近发现夜班女性患乳腺癌的风险显着增加，加上公众意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中的一个重要公共卫生问题、预防和治疗。从我们的新颖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（特别是针对夜班工人等高危人群）提供关键的一步。

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

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

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