Alternative Estrogen Replacement Therapy for Colon Canc*

描述(申请人提供)：植物学产品作为雌激素替代疗法(ERT)的替代品正变得越来越受欢迎。临床证据有力地支持ERT与降低绝经后女性结肠癌风险之间的关联。在对服用雌激素-孕激素联合替代疗法的妇女进行跟踪后，妇女健康倡议最近报告说，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，一半的人支持反向关联，另四分之一的人表明风险显著降低。尽管有这些发现，但很少有调查正在进行，以确定实现这一预防效果的机制。雌激素效应是通过与核受体结合而介导的，我们确定第二种雌激素受体亚型ERbeta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，结肠肿瘤组织中ERbeta mRNA的表达减少。此外，在ERbeta过表达后，人结肠癌细胞表现出增殖率降低和锚定无关生长。这些数据提示ERbeta可能介导了ERT的化学保护作用。正在测试的总体假设是，基于具有高ERbeta结合活性的植物雌激素的替代ERT将减少结肠癌的发生。本研究的目的是验证以下假设：(1)在人结肠癌细胞中过表达ERβ将通过干扰EGFR信号通路而降低体外(细胞培养中)和体内(小鼠异种生长)的致瘤表型，以及(2)富含植物雌激素的饮食将通过降低结肠上皮的增殖活性来减少实验诱导的异常隐窝病灶。这项应用的目标是确定激活ERbeta介导的反应如何调节人结肠癌细胞的生长，以及具有ERbeta选择性的红三叶草提取物是否可以减少致癌物引发的结肠癌发生。如果植物雌激素对结肠癌的发生具有化学预防作用，并且其机制与ERβ有关，那么这些数据将明显扩大我们对结肠癌的认识，并提供一种新的治疗策略。准确定位替代ERT如何抑制腺瘤-癌序列的能力也可能导致在预防女性患者癌症复发方面更有效的方法，以及在绝经后女性中开发更好的化学预防策略。这一假说的临床翻译潜力在于ERβ阳性的上皮细胞对植物雌激素的反应能力。这些结果还表明，基于选择性雌激素受体(ERbeta)治疗的化学预防策略具有额外的潜力。

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.