Neuroendocrine Influences on Mammary Cancer

描述（由申请人提供）：我们的实验室已经表明，褪黑激素 显著抑制ER+人乳腺癌的增殖，但不抑制ER-人乳腺癌的增殖 癌细胞，并调节表达和转录活性的 时代我们还证明了褪黑激素可以与视黄酸交叉作用， 酸（RA）信号通路，使得当用以下方案治疗时： 褪黑激素，然后在生理剂量的RA，乳腺癌细胞经历 凋亡在体内，褪黑激素和9-顺式-RA的组合被证明是有效的。 在抑制发展方面比单独的RA显著更有效， 诱导致癌物诱导的大鼠乳腺肿瘤消退。此外，委员会认为， 我们已经开发了新的数据，显示褪黑激素在肿瘤细胞中的作用， 通过梅拉/mt 1 G蛋白偶联受体介导， 这种受体的表达可以增强ER+乳腺肿瘤细胞对 褪黑素的生长抑制作用。这些数据导致我们目前 假设褪黑素的生长抑制作用是介导的， 至少部分是通过梅拉/mt 1褪黑激素受体，通过调节 类固醇/甲状腺激素受体信号通路的转录活性 (ERa和RAR/RXR），而梅拉/mt 1受体的过表达可 在ER+乳腺癌细胞中产生褪黑激素超敏感表型。到 为了验证这一假设，我们制定了以下具体目标：（1） 阐明梅拉/mt 1受体在发育中的重要性， 乳腺癌的进展，以及Mel所利用的信号通路 la/mt 1受体抑制MCF-7细胞增殖;（2）确定 梅拉/mt 1受体在控制乳腺癌细胞生长中的重要性 采用Mel Ⅰ a/mt 1基因切除和转基因过表达技术;（3） 为了确定过表达梅拉/mtl受体的MCF-7细胞是否表现出 增强对褪黑激素和RA定时方案的反应，并描绘 促进褪黑激素和RA信号通路之间的相互作用/串扰 在调节MCF-7细胞增殖和凋亡中的作用;（4）确定 褪黑激素和RA方案的最佳维甲酸、剂量和时间段 其诱导N-亚硝基甲基脲（NMU）诱导的大鼠 乳腺肿瘤褪黑激素通过哪些途径 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， 对于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.