Elucidating the mechanism of ERbeta in colon carcinogenesis

描述（由申请人提供）：目前还没有一种真正的预防或靶向治疗结肠癌的方法。然而，女性激素替代疗法出人意料地降低了结直肠癌的风险，口服避孕药的使用与这种疾病的发病率降低有关，并且雌二醇已被证明可以减少结肠肿瘤前病变的形成。雌激素受体（ERß）是人类结肠上皮中主要的雌激素受体；该基因的多态性与结肠癌发病率有关，其在肿瘤中的缺失与Dukes分期晚期和生存率较低有关。小鼠体内研究表明，ERß激动剂治疗可阻止肠道肿瘤的发展，而ERß的缺失会导致结肠腺瘤的增加。总的来说，这些观察结果清楚地指出ERß在结直肠癌中的保护作用。雌激素受体对健康和疾病有重要影响。它们可以被配体激活或灭活，是治疗靶向的理想候选者。存在选择性激活erβ的化合物，绕过雌激素通过激活ERα在男性和女性中诱导的不利影响。由于ERß具有作为结肠癌治疗靶点的巨大潜力，因此了解其作用的基本机制背景和鉴定其活性的生物标志物是至关重要的。PI的初步数据支持ERß在结肠中发挥这些作用的三个关键机制的存在。这三种机制是1)预测ERß和PROX1的相互作用，2)通过抑制NFkB/IL-6信号传导产生抗炎反应，3)通过调节miRNA介导的途径（包括miR17-92和miR-200a/b簇）产生抗肿瘤作用。该项目利用核受体和细胞信号中心的技术，详细了解ERß在结肠癌预防和治疗中的作用和潜力。本课题的总体目标是为利用ERß预防和治疗结肠癌提供新的机制基础。

DESCRIPTION (provided by applicant): A truly preventive or targeted therapy against colon cancer does not yet exist. However, hormone replacement therapy in women unexpectedly resulted in reduced risk of colorectal cancer, use of oral contraceptives is associated with a lower incidence of this disease, and estradiol has been shown to reduce the formation of preneoplastic lesions in the colon. Estrogen receptor beta (ERß) is the predominant estrogen receptor in the human colonic epithelium; polymorphisms in this gene are related to colon cancer incidence and its loss in tumors is related to advanced Dukes staging and poorer survival. In vivo mouse studies have demonstrated that ERß agonist treatment prevents intestinal tumor development and that deletion of ERß leads to an increase in colon adenomas. Collectively, these observations clearly point to a protective role for ERß in colorectal cancer. Estrogen receptors have significant consequences in health and diseases. They can be activated or inactivated by ligands, and are ideal candidates for therapeutic targeting. Compounds exist that selectively activate ERß, circumventing the adverse effects that estrogen induces in men and women through ERα activation. As ERß hold significant potential as a target for colon cancer therapy, it is essential to understand the basic mechanistic background of its action and to identify biomarkers of its activity. The PI's preliminary data supports the existence of three critical mechanisms whereby ERß exerts these effects in the colon. These three mechanisms are 1) a predicted ERß and PROX1 interaction, 2) an anti-inflammatory response via repression of NFkB/IL-6 signaling and 3) anti-oncogenic effects through the regulation of miRNA mediated pathways, including the miR17-92 and miR-200a/b clusters. This project takes advantage of the skills of the Center for Nuclear Receptors and Cell Signaling to provide a detailed understanding of ERß's role and potential in colon cancer prevention and treatment. The overall objective of this project is to provide the mechanistic basis for novel colo cancer prevention and therapy utilizing ERß.