Elucidating the mechanism of ERbeta in colon carcinogenesis

描述(申请人提供)：目前还不存在针对结肠癌的真正预防或靶向治疗。然而，女性的激素替代疗法出人意料地降低了患结直肠癌的风险，口服避孕药的使用与这种疾病的发病率较低有关，而且已有证据表明，雌二醇可以减少结肠癌前病变的形成。雌激素受体β(ER？)是人类结肠上皮细胞中最主要的雌激素受体，该基因的多态性与结肠癌的发生有关，肿瘤中ERβ基因的缺失与Dukes分期和较差的生存期有关。在小鼠体内的研究表明，ER激动剂治疗可以阻止肠道肿瘤的发展，ER的缺失会导致结肠腺瘤的增加。总而言之，这些观察结果清楚地表明ER在结直肠癌中具有保护作用。雌激素受体对健康和疾病有重大影响。它们可以被配体激活或失活，是治疗靶向的理想候选者。存在选择性地激活ER的化合物，从而避开雌激素通过激活ER而对男性和女性产生的不良影响。由于ER具有作为结肠癌治疗靶点的巨大潜力，了解其作用的基本机制背景并确定其活性的生物标志物是至关重要的。PI的初步数据支持ER在结肠中发挥这些作用的三种关键机制的存在。这三种机制是：1)预测的ER和PROX1的相互作用；2)通过抑制NFkB/IL-6信号转导而产生抗炎反应；3)通过调节miRNA介导的途径发挥抗肿瘤作用，包括miR17-92和miR-200a/b簇。本项目利用核受体和细胞信号传递中心的技术，详细了解ER？S在结肠癌防治中的作用和潜力。本项目的总体目标是为利用ER？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 (ER¿) 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 ER¿ agonist treatment prevents intestinal tumor development and that deletion of ER¿ leads to an increase in colon adenomas. Collectively, these observations clearly point to a protective role for ER¿ 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 ER¿, circumventing the adverse effects that estrogen induces in men and women through ER¿ activation. As ER¿ 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 ER¿ exerts these effects in the colon. These three mechanisms are 1) a predicted ER¿ 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 ER¿'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 ER¿.