Beta-Catenin/TCF Signaling in Breast Cancer

乳腺癌中的 β-连环蛋白/TCF 信号转导

• 批准号: 8109850
• 负责人: LOUISE R HOWE
• 金额: $ 34.02万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109850
• 关键词: Abbreviations; Address; Antineoplastic Agents; Breast; Breast Cancer Prevention; Breast Carcinoma; Breast Hyperplasia; Carcinoma; Cardiotoxicity; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Complex; Cultured Cells; Data; Development; Disease; Dominant-Negative Mutation; ERBB2 gene; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Exhibits; Foundations; Genetic Transcription; Goals; Human; Hyperplasia; Immunohistochemistry; In Situ Lesion; In Vitro; Individual; Ligands; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Molecular; Molecular Target; Monoclonal Antibodies; Mouse Strains; Mus; Mutation; Neoplasms; Noninfiltrating Intraductal Carcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Premalignant; Prevalence; Prevention; Prevention strategy; Preventive; Proteins; Recurrence; Reporter; Reporting; Research; Roche brand of trastuzumab; Role; Signal Pathway; Signal Transduction; System; TCF7L2 gene; Testing; Therapeutic Agents; Tissues; Transgenes; Tyrosine; Vertebrates; Woman; beta catenin; breast lesion; cancer initiation; carcinogenesis; design; efficacy testing; in utero; in vivo; interest; killings; malignant breast neoplasm; mammary gland development; novel; outcome forecast; overexpression; prevent; programs; receptor; tumor; tumor progression

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.

描述（由申请人提供）： 仅在美国，乳腺癌每年就会杀死40,000多名女性，但预防策略主要仅限于抗雌激素的方法和随之而来的局限性。我们假设β-catenin/TCF信号传导可能是预防乳腺癌的新目标。 Wnt/Beta-catenin信号通路的异常激活在人类癌症中广泛存在，已知是人类结肠直肠癌发生的起始事件。与明显的对比相比，β-catenin/TCF信号在乳腺癌中的作用知之甚少。已经观察到核细胞β-catenin在侵入性乳腺癌中观察到的。但是，尚未建立β-catenin稳定的机制。此外，尚未确定该途径在乳房前癌中的激活状态。我们的初步研究揭示了乳房增生和导管癌症（DCIS）病变中β-catenin/TCF途径激活的证据，这是侵入性乳腺癌的经常前体。此外，我们已经确定了HER2/NEU（人表皮生长因子受体2）与β-catenin/TCF信号传导之间的关系。这是尤其重要的，因为HER2/NEU在50-60％的人类DCIS挑战者中过度表达。因此，这项研究的目的是测试β-catenin/TCF信号在早期乳腺癌中的作用。特别是，我们旨在定义乳腺癌中该途径的激活状态，并测试β-catenin/TCF信号对乳腺肿瘤发育的需求。提出了三个具体目标来实现这些目标。 AIM 1旨在使用β-catenin免疫组织化学和TCF报告基因菌株来确定癌前乳腺病变和浸润性乳腺癌中β-catenin/TCF信号通路激活的程度。 AIM 2将询问HER2/NEU激活该途径的分子机制。在AIM 3中，将使用β-catenin/TCF-依赖性转录的主要负抑制剂来测试β-catenin/TCF信号在体内乳腺肿瘤形成的需求。意识到，Wnt/β-catenin信号的异常激活在人类肿瘤中非常普遍，这激发了人们对发展为β-catenin/tcf拮抗剂作为癌症治疗剂的巨大兴趣。在我们的研究中，积极的结果应该为测试这种β-catenin/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HER2/NEU与β-catenin/TCF信号之间的预测关系，因为这将允许特定的HER2定向靶向β-catenin/tcf拮抗剂对乳腺癌的靶向。我们的研究是开发β-catenin/TCF信号传导的重要第一步，这是预防癌前乳腺癌进展到浸润性乳腺癌的新目标。项目叙事的相关性仅在美国就每年在乳腺癌中死亡，但我们的乳腺癌预防策略的武器却不足。这项研究的目的是评估β-catenin/TCF信号传导，作为预防乳腺癌的新目标。 β-catenin/TCF信号传导途径经常在人类癌症中激活，并且在大肠癌中尤为重要。相反，该途径在早期乳腺癌发生中的作用知之甚少。我们建议检查β-蛋白/TCF信号在早期乳腺癌中的作用。首先，我们将确定癌前乳腺病变和侵入性乳腺癌中β-catenin/TCF信号通路的激活程度。其次，我们将测试该途径被激活的机制。第三，我们将测试体内乳腺肿瘤形成的途径的需求。重要的是，β-catenin/TCF拮抗剂已经在癌症治疗剂中发育。我们研究中的积极结果将为评估这种β-catenin/TCF拮抗剂预防人类乳腺癌的实用性奠定基础。