MELATONIN/ESTROGEN RESPONSE PATHWAY IN BREAST CANCER

描述：松果体激素，褪黑素，已多次被证明 抑制致癌物诱导的乳腺肿瘤形成。几个实验室已经 显示褪黑激素显著抑制雌激素的增殖 受体(ER)阳性，但不是ER阴性的人乳腺癌细胞。这个 申请人已证实褪黑素可降低 MCF-7细胞对ER基因的抑制作用 抄写。褪黑素对ER基因转录的抑制似乎 至少是褪黑素抑制乳腺癌的关键事件之一 然而，褪黑素调节细胞生长的途径(S) ER基因的转录还没有确定。最近的 膜结合型两种褪黑素受体的克隆 -蛋白质偶联褪黑素受体(Mel1a和Mel1b)和维甲酸Z 或孤儿受体(RZR-β/ROR-α)提供了对 褪黑素抑制乳腺肿瘤细胞生长的可能机制 调节ER的表达。希尔博士的最新研究，在这篇文章中描述 提案，提供证据证明褪黑激素之间存在串扰 和其他细胞信号通路(胰岛素和表皮生长因子) 调节内质网功能。考虑到中心和重要的有丝分裂原 雌激素在乳腺癌中的作用，褪黑素能够 调节内质网功能和表达证明其潜在用处 作为一种治疗剂。随着cDNAs探针可用于内质网， Mel1a、Mel1b、RoRα和各种雌激素调节基因、抗体 Mel1a受体和ER，以及3.5kb的上游调控片段 希尔博士计划从MCF-7乳腺癌细胞中克隆ER基因的区域 扩展他对褪黑素参与的机制的分析(S) 通过检测其对ER的影响来调节乳腺癌细胞的生长 功能和表达。在这方面要解决的主要问题 应用是：(1)确定褪黑素受体、Mel1a和/或 ROR-α在乳腺癌细胞中表达，以及它们是否可以 褪黑素或雌激素的调节；(2)确定细胞信号转导 途径(S)转导褪黑素对ER功能的调节；和(3) 确定褪黑素与神经细胞相互作用的分子机制(S) ER基因5‘侧翼区抑制ER基因转录。最近的 公众使用褪黑素作为睡眠辅助的增加，加在一起 褪黑素对雌激素反应途径的影响，特别是在 乳腺癌，但也在其他内分泌反应性肿瘤中，进一步 证实了更清楚地了解影响的迫切需要 和褪黑素的作用机制(S)。

DESCRIPTION: The pineal hormone, melatonin, has repeatedly been shown to inhibit carcinogen-induced mammary tumorigenesis. Several laboratories have shown that melatonin significantly inhibits the proliferation of estrogen receptor (ER)-positive, but not ER-negative human breast cancer cells. The applicant has established that melatonin decreases overall ER levels in MCF-7 breast tumor cells through its suppressive effects on ER gene transcription. Melatonin's suppression of ER gene transcription appears to be at least one of the key events by which melatonin inhibits breast cancer cell growth; however, the pathway(s) through which melatonin regulates the transcription of the ER gene has not yet been determined. The recent cloning of two types of melatonin receptors, the membrane bound -protein-coupled melatonin receptors (Mel1a and Mel1b) and retinoic acid Z or orphan receptors (RZR-beta/ROR-alpha) provides fresh insight into the possible mechanisms by which melatonin inhibits breast tumor cell growth and regulates ER expression. Dr. Hill's most recent studies, described in this proposal, provide evidence that there is cross-talk between the melatonin and other cellular signaling pathways (insulin and epidermal growth factor) to modulate ER function. Considering the central and important mitogenic role of estrogen in breast cancer, the fact that melatonin is able to regulate both ER function and expression attests to its potential usefulness as a therapeutic agent. With the availability of cDNA probes to the ER, Mel1a, Mel1b, ROR alpha and various estrogen regulated genes, antibodies to the Mel1a receptor and ER, and a 3.5-kb fragment of the upstream regulatory region of the ER gene cloned from MCF-7 breast cancer cells, Dr. Hill plans to expand his analysis of the mechanism(s) involved in melatonin's regulation of breast cancer cell growth by examining its effects on ER function and expression. The major issues to be addressed in this application are: (1) to determine which melatonin receptors, Mel1a and/or ROR-alpha, are expressed in breast cancer cells and whether they can be modulated by melatonin or estrogen; (2) to determine the cellular signaling pathway(s) transducing melatonin's modulation of ER function; and (3) to determine the molecular mechanism(s) by which melatonin interacts with the ER gene 5'-flanking region to repress ER gene transcription. The recent increase in melatonin use as a sleep aid by the general public, combined with melatonin's effects on the estrogen-response pathway, particularly in breast cancer, but also in other endocrine-responsive neoplasms, further substantiates the immediate need for a clearer understanding of the effects and mechanism(s) of melatonin's actions.