Beta-Catenin/TCF Signaling in Breast Cancer

描述（由申请人提供）： 仅在美国，每年就有超过40，000名女性死于乳腺癌，但预防策略主要限于抗雌激素方法及其伴随的局限性。我们推测β-连环蛋白/TCF信号可能是乳腺癌预防的新靶点。Wnt/β-连环蛋白信号通路的异常激活在人类癌症中广泛存在，并且已知是人类结直肠癌发生中的起始事件。与此形成鲜明对比的是，β-连环蛋白/TCF信号在乳腺癌中的作用知之甚少。在高比例的浸润性乳腺癌中观察到核质β-连环蛋白。然而，β-连环蛋白稳定的机制尚未建立。此外，尚未确定乳腺癌前病变中该通路的激活状态。我们的初步研究揭示了β-连环蛋白/TCF通路在乳腺增生和导管原位癌（DCIS）病变中激活的证据，这些病变是浸润性乳腺癌的常见前兆。此外，我们已经确定了HER 2/neu（人表皮生长因子受体2）和β-连环蛋白/TCF信号之间的关系。这是特别重要的，因为HER 2/neu在50-60%的人DCIS前癌中过表达。因此，本研究的目标是测试β-连环蛋白/TCF信号传导在早期乳腺肿瘤中的作用。特别是，我们的目标是确定乳腺癌前病变中该通路的激活状态，并测试乳腺肿瘤发展对β-连环蛋白/TCF信号传导的需求。为实现这些目标，提出了三个具体目标。目的1旨在使用β-连环蛋白免疫组织化学和TCF报告小鼠品系来确定β-连环蛋白/TCF信号通路在癌前乳腺病变和浸润性乳腺癌中的激活程度。AIM 2将研究HER 2/neu激活该通路的分子机制。在AIM 3中，β-连环蛋白/TCF依赖性转录的显性负抑制因子将用于测试体内乳腺肿瘤形成对β-连环蛋白/TCF信号传导的需求。认识到Wnt/β-连环蛋白信号传导的异常激活在人类肿瘤形成中非常普遍，激发了开发β-连环蛋白/TCF拮抗剂作为癌症治疗剂的巨大兴趣。我们研究的阳性结果应该为测试这种β-连环蛋白/TCF拮抗剂预防乳腺癌的功效铺平道路。在这方面，重要的是DCIS中HER 2/neu和β-连环蛋白/TCF信号传导之间的预测关系，因为这将允许β-连环蛋白/TCF拮抗剂特异性HER 2靶向乳腺癌前病变。我们的研究是开发β-连环蛋白/TCF信号传导作为预防癌前乳腺病变进展为浸润性乳腺癌的新靶点的重要第一步。仅在美国，每年就有超过40，000名女性死于乳腺癌，但我们的乳腺癌预防策略远远不够。本研究的目的是评估β-连环蛋白/TCF信号传导作为乳腺癌预防的新靶点。β-连环蛋白/TCF信号通路在人类癌症中经常被激活，并且已知在结直肠癌中特别重要。相反，这一途径在早期乳腺癌发生中的作用知之甚少。我们建议研究β-连环蛋白/TCF信号在早期乳腺癌中的作用。首先，我们将确定β-连环蛋白/TCF信号通路在乳腺癌前病变和浸润性乳腺癌中的激活程度。其次，我们将测试激活这条通路的机制。第三，我们将测试体内乳腺肿瘤形成对该途径的要求。重要的是，β-连环蛋白/TCF拮抗剂已经在开发中作为癌症治疗剂。本研究的阳性结果将为评价β-连环蛋白/TCF拮抗剂预防人类乳腺癌的效用奠定基础。

DESCRIPTION (provided by applicant): Breast cancer kills over 40,000 women every year in the US alone, yet preventive strategies are predominantly restricted to anti-estrogenic approaches with their attendant limitations. We hypothesize that beta-catenin/TCF signaling may be a novel target for breast cancer prevention. Aberrant activation of the Wnt/beta-catenin signaling pathway is widespread in human cancers, and is known to be an initiating event in human colorectal carcinogenesis. In marked contrast, the role of beta-catenin/TCF signaling in breast cancer is poorly understood. Nucleocytoplasmic beta-catenin has been observed in a high proportion of invasive breast carcinomas. However, the mechanism of beta-catenin stabilization has not been established. Furthermore, the activation status of this pathway in precancers of the breast has not been determined. Our preliminary studies have revealed evidence of beta-catenin/TCF pathway activation in breast hyperplasias and ductal carcinoma in situ (DCIS) lesions, frequent precursors to invasive breast cancer. Additionally, we have identified a relationship between HER2/neu (human epidermal growth factor receptor 2) and beta-catenin/TCF signaling. This is of particular importance because HER2/neu is overexpressed in 50-60% of human DCIS precancers. Therefore, the goal of this research is to test the role of beta-catenin/TCF signaling in early breast neoplasia. In particular, we aim to define the activation status of this pathway in breast precancers, and to test the requirement for beta-catenin/TCF signaling for breast tumor development. Three specific aims are proposed to achieve these goals. AIM 1 is designed to determine the extent of beta-catenin/TCF signaling pathway activation in precancerous breast lesions and invasive breast cancers, using beta-catenin immunohistochemistry and TCF reporter mouse strains. AIM 2 will interrogate the molecular mechanisms by which HER2/neu activates this pathway. In AIM 3, a dominant negative suppressor of beta-catenin/TCF- dependent transcription will be used to test the requirement for beta-catenin/TCF signaling for breast tumor formation in vivo. The realization that aberrant activation of Wnt/beta-catenin signaling is highly prevalent in human neoplasia has stimulated enormous interest in developing beta-catenin/TCF antagonists as cancer therapeutic agents. Positive results in our study should pave the way for testing the efficacy of such beta-catenin/TCF antagonists for breast cancer prevention. Important in this respect is the predicted relationship between HER2/neu and beta-catenin/TCF signaling in DCIS, since this would allow specific HER2- directed targeting of beta-catenin/TCF antagonists to breast precancers. Our research is an essential first step in the development of beta-catenin/TCF signaling as a novel target for the prevention of progression of precancerous breast lesions to invasive breast cancer. PROJECT NARRATIVE RELEVANCE Over 40,000 women die from breast cancer every year in the US alone, and yet our arsenal of breast cancer prevention strategies is woefully inadequate. The goal of this research is to evaluate beta-catenin/TCF signaling as a novel target for breast cancer prevention. The beta-catenin/TCF signaling pathway is frequently activated in human cancer, and is known to be particularly important in colorectal cancer. In contrast, the role of this pathway in early breast carcinogenesis is poorly understood. We propose to examine the role of beta-catenin/TCF signaling in early breast cancer. Firstly, we will determine the extent of beta-catenin/TCF signaling pathway activation in precancerous breast lesions and invasive breast cancers. Secondly, we will test the mechanism by which this pathway is activated. Thirdly, we will test the requirement for this pathway for breast tumor formation in vivo. Importantly, beta-catenin/TCF antagonists are already in development as cancer therapeutic agents. Positive results in our study would lay the foundation for evaluating the utility of such beta-catenin/TCF antagonists for preventing human breast cancer.