Alternative Estrogen Replacement Therapy for Colon Canc*

描述（由申请人提供）：植物产品作为雌激素替代疗法（ERT）的替代品越来越受欢迎。临床证据强烈支持ERT与绝经后妇女结肠癌风险降低之间的联系。在对服用雌激素-黄体酮联合替代疗法的妇女进行随访后，妇女健康倡议组织最近报告说，与服用安慰剂的妇女相比，结直肠癌病例减少了37%。在另外20项已发表的研究中，有一半支持反向关联，另有四分之一显示风险显著降低。尽管有这些发现，但很少有调查正在进行中，以确定实现这种预防效果的机制。雌激素的作用是通过结合核受体介导的，我们确定了第二种雌激素受体亚型，erβ，是在结肠上皮中发现的亚型。我们的研究还显示，与女性患者的正常粘膜相比，结肠肿瘤中ERbeta mRNA的表达减少。此外，过度表达ERbeta后，人类结肠癌细胞表现出增殖率降低和锚定独立生长。这些数据表明ERbeta可能介导ERT的化学保护作用。总的假设是，基于高erβ结合活性的植物雌激素的替代ERT将减少结肠癌的发生。我们提出了验证以下假设的具体目的：(1)人结肠癌细胞中ERbeta的过表达会通过干扰EGFR信号通路，在体外（培养细胞）和体内（小鼠的异种生长）降低致瘤表型；(2)富含植物雌激素的饮食会通过降低结肠上皮的增殖活性，减少实验诱导的异常隐窝灶。本应用程序的目的是确定erβ介导的反应的激活如何调节人类结肠癌细胞的生长，以及具有erβ选择性的红三叶草提取物是否可以减少致癌物质引发的结肠肿瘤发生。如果植物雌激素显示出对结肠癌发展的化学预防作用，其机制与ERbeta有关，这些数据将明显扩大我们对结肠癌的认识，并提供新的治疗策略。查明替代ERT如何抑制腺瘤-癌序列的能力也可能导致更有效的方法来预防女性患者的癌症复发，以及为绝经后妇女制定更好的化学预防策略。这一假说的临床转化潜力在于ERbeta阳性上皮细胞对植物雌激素的反应能力。这些结果也提示了基于选择性雌激素受体（erβ）治疗的化学预防策略的额外潜力。

DESCRIPTION (provided by applicant): Botanical products are becoming increasingly popular as alternatives to estrogen replacement therapy (ERT). Clinical evidence strongly supports an association between ERT and reduced risk of colon cancer in postmenopausal women. After follow-up of women taking combined estrogen-progestin replacement therapy, the Women's Health Initiative recently reported a 37% reduction in colorectal cancer cases compared to women on placebo. In another 20 published studies, half support an inverse association and another quarter shows a significant reduction in risk. Despite these findings, few investigations are underway to determine the mechanisms by which this preventive effect is achieved. Estrogenic effects are mediated by binding to a nuclear receptor and we determined that the second estrogen receptor subtype, ERbeta, is the subtype found in the colonic epithelium. Our studies also showed reduced expression of ERbeta mRNA in colon tumors compared to normal mucosa in female patients. Furthermore, following over-expression of ERbeta, human colon cancer cells displayed reduced proliferation rates and anchorage independent growth. These data imply that ERbeta could mediate the chemoprotective effects for ERT. The overall hypothesis being tested is that alternative ERT based on phytoestrogens with high ERbeta binding activity will reduce colon carcinogensis. Specific aims are proposed to test the following hypotheses: (1) Overexpression of ERbeta in human colon cancer cells will decrease tumorigenic phenotype in vitro (cells in culture) and in vivo (xenograph growth in mice) by interference of EGFR signaling pathways, and (2) A phytoestrogen-enriched diet will reduce experimentally induced aberrant crypt foci by decreasing proliferative activity in the colonic epithelium. The goal of this application is to define how activation of ERbeta-mediated responses can modulate human colon cancer cell growth and whether a red clover extract with ERbeta-selectivity can decrease carcinogen initiated colon tumorigenesis. If phytoestrogens show a chemopreventive effect on colon cancer development and the mechanism is related to ERbeta, these data would clearly expand our understanding of colon cancer and provide a new therapeutic strategy. The ability to pinpoint how an alternative ERT inhibits the adenoma-carcinoma sequence could also lead to more effective methods in preventing cancer recurrence in female patients, as well as developing better chemoprevention strategies in post-menopausal women. The clinical translational potential of this hypothesis lies in the ability of ERbeta positive epithelial cells to respond to phytoestrogens. These results would also suggest additional potential for chemoprevention strategies based on selective estrogen receptor (ERbeta) therapies.