Neuroendocrine Influences on Mammary Cancer

描述(申请人提供)：我们的实验室已经证明褪黑激素 显著抑制ER+的增殖，但不能抑制ER-人乳房 并调节肿瘤细胞的表达和转录活性。 时代。我们还证明了褪黑素可以与维甲酸进行交叉对话。 酸(RA)信号通路，这样，当用 褪黑素和RA在生理剂量下，乳腺癌细胞经历 细胞凋亡。在体内，褪黑素和9-顺式维甲酸的结合被证明是 明显比单独使用RA更有效地抑制发展和 诱导致癌物诱导的大鼠乳腺肿瘤消退。此外， 我们开发的新数据表明，褪黑素在肿瘤细胞中的作用是 通过Mella/MT1G蛋白偶联受体介导，并过度表达 该受体可增强ER+乳腺肿瘤细胞对 褪黑素的生长抑制作用。这些数据导致了我们目前的 假设褪黑素的生长抑制作用是通过中介实现的，在 至少部分是通过Mella/MT1褪黑素受体调节 类固醇/甲状腺激素受体信号通路的转录活性 (ERA和RAR/RXR)，Mella/MT1受体过表达可以 在ER+乳腺癌细胞中产生褪黑素超敏表型。至 为了验证这一假设，我们制定了以下具体目标：(1) 阐明Mella/MT1受体在胚胎发育和发育中的重要性 乳腺癌的进展与MEL所利用的信号通路(S) LA/MT1受体抑制MCF-7细胞增殖；(2)确定 Mella/MT1受体在控制乳腺癌细胞生长中的重要性 使用Mel I a/MT1基因去除和转基因过表达技术；(3) 为了确定过表达Mella/MTL受体的MCF-7细胞是否表现出 对褪黑素和RA定时方案的增强反应，并描绘 褪黑素与类风湿关节炎信号通路的相互作用/串扰 调节MCF-7细胞的增殖和凋亡；以及(4)确定 褪黑素和类风湿关节炎方案的最佳维甲酸、剂量和时间周期 能使N-亚硝基甲基脲(NMU)诱导的大鼠最大回落 乳腺肿瘤。褪黑素途径的研究进展 抑制乳腺肿瘤的发展和生长，并与 其他激素反应途径，如雌激素和维甲酸途径，是 对未来内分泌治疗策略的发展至关重要 和预防乳腺癌。

DESCRIPTION (provided by applicant): Our laboratory has shown that melatonin significantly inhibits the proliferation of ER+, but not ER- human breast cancer cells, and modulates the expression and transcriptional activity of the ERa. We have also demonstrated that melatonin can cross-talk with the retinoic acid (RA) signaling pathway, such that, when treated with a regimen of melatonin followed by RA at physiologic doses, breast cancer cells undergo apoptosis. In vivo, the combination of melatonin and 9-cis-RA was shown to be significantly more effective than RA alone at inhibiting the development and inducing the regression of carcinogen-induced rat mammary tumors. Furthermore, we have developed new data showing that melatonin's effects in tumor cells are mediated via the Mella/mt1 G protein-coupled receptor, and that overexpression of this receptor can enhance the response of ER+ breast tumor cells to the growth inhibitory effects of melatonin. These data led to our current hypothesis that the growth-inhibitory actions of melatonin are mediated, at least in part, through the Mella/mt1 melatonin receptor via modulation of the transcriptional activity of steroid/thyroid hormone receptor signaling pathways (ERa and RAR/RXR), and that overexpression of the Mella/mt1 receptor can generate a melatonin supersensitive phenotype in ER+ breast cancer cells. To test this hypothesis, we have developed the following Specific Aims: (1) To elucidate the importance of the Mella/mt1 receptor in the development and progression of breast cancer, and the signaling pathway(s) utilized by the Mel la/mt1 receptor to suppress MCF-7 cell proliferation; (2) To define the importance of the Mella/mt1 receptor in controlling breast cancer cell growth using Mel I a/mt1 gene ablation and transgenic overexpression techniques; (3) To determine if MCF-7 cells overexpressing the Mella/mtl receptor exhibit an enhanced response to the timed regimen of melatonin and RA, and to delineate further the interaction/cross-talk between melatonin and RA signaling pathways in regulating MCF-7 cell proliferation and apoptosis; and (4) To determine the optimal retinoid, dosage, and time period for the regimen of melatonin and RA which induces maximal regression of N-nitrosomethylurea (NMU)-induced rat mammary tumors. The characterization of the pathways by which melatonin inhibits the development and growth of breast tumors, and cross-talks with other hormone response pathways, such as the estrogen and retinoid pathways, is essential for the development of future endocrine strategies in the treatment and prevention of breast cancer.