Bile Acid and Estrogen Receptors in Colon Cancer

描述（由申请人提供）：结直肠癌是美国癌症死亡的第二大常见原因。高脂肪饮食是结肠癌的一个重要危险因素;相反，雌激素可以防止结肠癌的发生。脂肪饮食的有害作用和雌激素的有益作用的机制尚不清楚。然而，一个令人信服的假设是，高脂肪饮食通过增加结肠中胆汁酸的浓度而促进癌变，胆汁酸刺激细胞增殖并作为肿瘤促进剂。有强有力的流行病学和动物模型数据将胆汁酸浓度升高与结直肠癌联系起来。我们提出了一个统一的假设，其中胆汁酸的促癌作用和雌激素的抗癌作用分别通过胆汁酸受体FXR和雌激素受体β（ER β）介导。这两种受体都是配体激活转录因子的类固醇/甲状腺激素受体家族的成员，并在结肠中大量表达。在所提出的模型中，FXR的活化诱导另一种称为SHP的核受体的表达，其抑制ER β的抗增殖作用。在初步数据中，它表明，FXR的激活导致结肠粘膜的过度增殖，这种效果需要SHP。值得注意的是，SHP的诱导与体外和体内ER β的抑制相关。在这项提议中，FXR，SHP和ER β在结肠癌发生中的作用将被研究。在具体目标1中，将检查FXR和SHP在胆汁酸促进的增殖和结肠癌发生中的作用。在具体目标2中，将研究雌激素在结肠中保护作用的分子机制。在具体目标3中，将检查胆汁酸抑制ER β表达的机制。这些研究将为胆汁酸、雌激素和结直肠癌发生之间的复杂关系提供重要的见解。此外，由于FXR和ER β都可以通过小分子配体调节，这些研究可能揭示治疗和预防结肠癌的新机会。

DESCRIPTION (provided by applicant): Colorectal cancer is the second most common cause of cancer death in the United States. High fat diets are an important risk factor for colon cancer; conversely, estrogens protect against colon carcinogenesis. The mechanisms underlying the detrimental actions of fatty diets and the beneficial effects of estrogens are unclear. However, one compelling hypothesis is that fatty diets contribute to carcinogenesis by increasing colonic concentrations of bile acids, which stimulate cell proliferation and act as tumor promoters. There is strong epidemiological and animal model data linking elevated bile acid concentrations to colorectal cancer. We propose a unifying hypothesis in which the pro-carcinogenic effects of bile acids and the anti- carcinogenic actions of estrogens are mediated through the bile acid receptor FXR and the estrogen receptor beta (ERbeta), respectively. Both receptors are members of the steroid/thyroid hormone receptor family of ligand-activated transcription factors and are abundantly expressed in colon. In the proposed model, activation of FXR induces expression of another nuclear receptor, termed SHP, which suppresses the anti- proliferative actions of ERbeta. In preliminary data, it is shown that activation of FXR causes hyperproliferation of the colonic mucosa and that this effect requires SHP. Notably, induction of SHP correlates with repression of ERbeta both in vitro and in vivo. In this proposal, the roles of FXR, SHP, and ERbeta in colon carcinogenesis will be studied. In Specific Aim 1, the roles of FXR and SHP in proliferation and colon carcinogenesis promoted by bile acids will be examined. In Specific Aim 2, the molecular mechanisms underlying the protective actions of estrogens in colon will be studied. In Specific Aim 3, the mechanism whereby bile acids repress ERbeta expression will be examined. These studies will provide important insights into the complex relationship between bile acids, estrogens, and colorectal carcinogenesis. Moreover, since both FXR and ERbeta can be regulated by small molecule ligands, these studies may reveal novel opportunities for treating and preventing colon cancer.