Using Nonclassical Estrogen Signaling to Prevent Melanoma

项目摘要：尽管黑色素瘤治疗取得了进展，但只有33%的晚期患者 疾病对最有效的治疗有反应，平均生存期只有23个月。数以百万计的人 有红色头发或浅色皮肤色素沉着的人患黑色素瘤的风险特别高。虽然战略是为了 降低这种风险是缺乏的，我们最近的发现表明黑色素瘤的发病率可能是 通过药物激活G蛋白雌激素受体(GPER)而减弱，GPER是一种 黑素细胞的活性与经典的雌激素受体(ERα/β)完全不同。尽管在那里 是没有被批准的靶向GPER的药物，GPER在黑素细胞中通过选择性合成的 不具有任何经典雌激素活性的化合物(G-1)。我们最近确定 体内药物GPER激活主要通过诱导末梢抑制已建立的黑色素瘤 癌细胞的分化。我们的初步研究表明，G-1介导的GPER激活 在黑素细胞中诱导长期的表观遗传变化，以防止未来的黑色素瘤，同时允许 皮肤黑素细胞继续正常运作。 在目标I中，我们将使用原代人类黑素细胞来确定特定的组蛋白修饰酶。 诱导表观遗传转录记忆所必需的，以维持细胞的高度状态 GPER短暂激活后的分化，并测试HDAC抑制是否增强了 GPER激动剂的分化作用。 在AIM II中，我们将验证初步结果，这些结果表明GPER信号诱导了 促进DNA修复，从而最大限度地减少紫外线(UV)后DNA突变的积累 曝光。我们将确定GPER下游调节改进DNA的机制(S) 损害反应，这可能有助于突出额外的治疗靶点。 在Aim III中，我们将使用人类和小鼠黑色素瘤模型来直接测试G-1 激活GPER促进体内紫外线照射后DNA修复并抑制黑色素瘤 发展。

Project summary: Despite advances in melanoma treatment, only 33% of patients with advanced disease respond to the most effective therapy and mean survival is only 23 months. Millions of people with red hair, or light skin pigmentation have an especially high melanoma risk. Although strategies to decrease this risk are lacking, our recent discoveries suggest that melanoma incidence may be diminished by pharmacologically activating the G-Protein Estrogen Receptor (GPER), a protein on melanocytes with activity completely distinct from the classic estrogen receptor (ERα/β). Although there are no approved drugs that target GPER, GPER is activated in melanocytes by a selective synthetic compound (G-1) that does not have any classic estrogen activity. We recently determined that pharmacologic GPER activation in vivo inhibits established melanomas, largely by inducing terminal differentiation in cancer cells. Our preliminary studies now suggest that G-1 mediated GPER activation in melanocytes induces long-term epigenetic changes that prevent future melanoma, while allowing skin melanocytes to continue to function normally. In Aim I we will use primary human melanocytes to determine the specific histone modifying enzymes required for inducing epigenetic transcriptional memory that maintains a heightened state of cellular differentiation after transient GPER activation, and test whether HDAC inhibition potentiates the differentiation effects of the GPER agonist. In Aim II we will validate preliminary results suggesting that GPER signaling induces pathways that promote DNA repair, and thereby minimizes the accumulation of DNA mutations after ultraviolet (UV) exposure. We will determine the mechanism(s) downstream of GPER that mediate the improved DNA damage response, which may help highlight additional therapeutic targets. In Aim III we will use both human and mouse melanoma models to directly test whether G-1 activation of GPER promotes DNA repair after UV exposure in vivo, and inhibits melanoma development.