Phytonutrient Suppression of Wnt Signaling in Cancer

植物营养素抑制癌症中的 Wnt 信号传导

• 批准号: 6869257
• 负责人: AMY S. YEE
• 金额: $ 32.22万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869257
• 关键词: RNA interference; biological signal transduction; breast neoplasms; cancer prevention; carcinogenesis; cell communication molecule; cell line; chemoprevention; cyclins; dietary supplements; enzyme activity; flavonoids; laboratory mouse; mitogen activated protein kinase; mouse mammary tumor virus; neoplasm /cancer invasiveness; neoplastic growth; nutrition aspect of cancer; nutrition related tag; prostaglandin endoperoxide synthase; protooncogene; tea; transcription factor; xenotransplantation

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(申请人提供)：本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。随着更早的发现和更好的生存，新的临床挑战是对可能的复发和/或晚期疾病的治疗和预防策略。因此，更好地了解调控早期乳腺癌增殖增加和侵袭性增加的机制将促进对早期乳腺癌预后和预防策略的新分子靶点的了解。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，并已将植物营养素分离出来作为生物活性食品成分。然而，合理地应用于癌症预防需要对选定的癌症背景下的分子机制有精确的了解。我们的长期目标是促进对分子和细胞机制的了解，通过这些分子和细胞机制，植物营养素可以调节癌症中失调的特定信号通路。不同的遗传学研究强调，构成Wnt信号与乳腺癌和许多癌症有关。然而，在阻断构成Wnt信号的策略上存在着知识差距。流行病学研究将饮用绿茶与减少早期乳腺癌的复发联系在一起。这项建议将在分子和营养专业知识之间架起桥梁，以发现可能阻止构成Wnt信号并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性方面的作用。我们的初步结果表明，EGCG通过诱导HBP1转录抑制因子有效地抑制了Wnt信号，HBP1是Wnt信号的抑制因子。抑制Wnt信号的分子基础将在基于细胞和动物的Wnt信号模型中进一步定义。在基于细胞的研究中，将讨论Wnt信号与乳腺细胞侵袭性的关系。以EGCG机制为背景，在MMTV-WNT和异种移植小鼠模型中，饮食中添加EGCG将被用于抑制明确的乳腺肿瘤发生，作为临床前研究。这些研究还可能为未来的临床研究定义新的生物标记物，并促进对HBP1作为乳腺细胞侵袭性可能调节因子的认识。总而言之，这些研究应该为未来使用EGCG和其他植物营养素预防早期乳腺癌的临床研究创造有价值的基础。