Phytonutrient Suppression of Wnt Signalling in Cancer

植物营养素抑制癌症中的 Wnt 信号传导

• 批准号: 7547748
• 负责人: AMY S. YEE
• 金额: $ 31.78万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547748
• 关键词: Address; Animals; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Prevention; Cell Cycle; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Consumption; Cyclin D1; Data; Dietary Supplementation; Disease; Early Diagnosis; Early treatment; Epidemiologic Studies; Epigallocatechin Gallate; Food; Foundations; Future; Gene Mutation; Gene Targeting; Genes; Genetic; Goals; Green tea; Human; Investigation; Knowledge; Lead; Link; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Measures; Mediating; Modeling; Molecular; Molecular Target; Mus; Noninfiltrating Intraductal Carcinoma; Nutritional; Pathway interactions; Patients; Prevention; Prevention strategy; RNA Interference; Recurrence; Research Personnel; Risk; Role; Screening procedure; Signal Pathway; Signal Transduction; Specific qualifier value; Staging; Testing; Transcription Repressor/Corepressor; Variant; Xenograft Model; Xenograft procedure; advanced disease; base; bioactive food component; breast tumorigenesis; cancer prevention; cancer risk; cationic antimicrobial protein CAP 37; cell growth; cyclooxygenase 2; inhibitor/antagonist; loss of function; malignant breast neoplasm; mouse model; pre-clinical; prevent; prognostic; programs; response; tool; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The framework of this application will be the mechanisms of early breast cancers that are characterized by increased proliferation and of invasiveness. With the advent of earlier detection and better survival, new clinical challenges are the treatment and prevention strategies for possible recurrent and/or advanced disease. Thus, a better understanding of the mechanisms that regulate the increased proliferation and of invasiveness in early breast cancers will advance knowledge for new molecular targets for prognostic and preventative strategies for early breast cancers. For cancer prevention, the use of natural compounds or dietary strategies is an attractive possibility. Epidemiological studies have identified certain foods associated with reduced cancer risk and have resulted in the isolation of phytonutrients as bioactive food components. However, rational applications for cancer prevention require precise knowledge of the molecular mechanisms in selected cancer contexts. Our long-term goal is to advance the knowledge on the molecular and cellular mechanisms by which phytonutrients may modulate specific signaling pathways that are dysregulated in cancer. Diverse genetic studies have highlighted that constitutive Wnt signaling is linked to breast and numerous cancers. However, a gap in knowledge exists on strategies to block constitutive Wnt signaling. Epidemiological studies have linked green tea consumption to a reduced recurrence of early breast cancers. This proposal will bridge molecular and nutritional expertise to discover new strategies that may block constitutive Wnt signaling and delay mammary tumorigenesis. The focus of this application is an investigation of the green tea phytonutrient EGCG [(-) epigallo-catechin gallate] in suppressing proliferation and invasiveness in early breast cancer. Our preliminary results indicate that EGCG is efficient at suppressing Wnt signaling by inducing the HBP1 transcriptional repressor, which is an inhibitor of Wnt signaling. The molecular basis for suppression of Wnt signaling will be further defined in cell- and animal-based models of Wnt signaling. In cell-based studies, the involvement of Wnt signaling in breast cell invasiveness will be addressed. With the EGCG mechanisms as a backdrop, dietary supplementation with EGCG will be used to suppress defined mammary tumorigenesis in MMTV-Wnt and xenograft mouse models as a pre-clinical investigation. These studies may also define new biomarkers for future clinical studies and advance knowledge on HBP1 as a possible regulatory factor in breast cell invasiveness. Together, these studies should create a valuable foundation for future clinical studies with EGCG and other phytonutrients for early breast cancer prevention.

描述（由申请人提供）：本次申请的框架将是早期乳腺癌的机制，其特征是增殖增加和侵袭性增加。随着早期发现和生存率的提高，新的临床挑战是治疗和预防可能复发和/或晚期疾病的策略。因此，更好地了解早期乳腺癌中增殖和侵袭性增加的调节机制将促进早期乳腺癌预后和预防策略的新分子靶点的认识。对于癌症预防，使用天然化合物或饮食策略是一个有吸引力的可能性。流行病学研究已经确定了某些与降低癌症风险有关的食物，并已将植物营养素作为生物活性食品成分进行了分离。然而，癌症预防的合理应用需要对特定癌症背景下的分子机制有精确的了解。我们的长期目标是推进植物营养素调节癌症中失调的特定信号通路的分子和细胞机制的知识。不同的遗传研究强调，组成型Wnt信号与乳腺癌和许多癌症有关。然而，在阻断本构Wnt信号的策略方面存在知识空白。流行病学研究表明，饮用绿茶可以降低早期乳腺癌的复发率。该建议将分子和营养专业知识结合起来，发现可能阻断构成性Wnt信号传导和延迟乳腺肿瘤发生的新策略。本应用的重点是研究绿茶植物营养素EGCG[（-）表没食子儿茶素没食子酸酯]在抑制早期乳腺癌增殖和侵袭中的作用。我们的初步结果表明，EGCG通过诱导HBP1转录抑制因子（Wnt信号的抑制剂）有效抑制Wnt信号。Wnt信号抑制的分子基础将在基于细胞和动物的Wnt信号模型中进一步确定。在基于细胞的研究中，将讨论Wnt信号在乳腺细胞侵袭中的作用。以EGCG机制为背景，在MMTV-Wnt和异种移植小鼠模型中，膳食补充EGCG将被用于抑制明确的乳腺肿瘤发生，作为一项临床前研究。这些研究也可能为未来的临床研究确定新的生物标志物，并推进HBP1作为乳腺细胞侵袭性可能的调节因子的认识。总之，这些研究应该为EGCG和其他植物营养素预防早期乳腺癌的临床研究奠定有价值的基础。