Phytonutrient Suppression of Wnt Signalling in Cancer

描述（由申请人提供）：本申请的框架将是以增殖增加和侵袭性为特征的早期乳腺癌的机制。随着早期检测和更好的生存率的出现，新的临床挑战是对可能复发和/或晚期疾病的治疗和预防策略。因此，更好地了解机制，调节增加的增殖和侵袭性的早期乳腺癌将推进知识的新的分子靶点的预后和预防策略的早期乳腺癌。对于癌症预防，使用天然化合物或饮食策略是一种有吸引力的可能性。流行病学研究已经确定了某些食物与降低癌症风险有关，并导致植物营养素作为生物活性食物成分的分离。然而，癌症预防的合理应用需要在选定的癌症背景下的分子机制的精确知识。我们的长期目标是推进植物营养素可能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。不同的遗传学研究已经强调了组成性Wnt信号传导与乳腺癌和许多癌症有关。然而，在阻断组成性Wnt信号传导的策略方面存在知识差距。流行病学研究表明，饮用绿色茶可以减少早期乳腺癌的复发。该提案将弥合分子和营养专业知识，以发现可能阻断组成性Wnt信号传导和延迟乳腺肿瘤发生的新策略。本申请的重点是研究绿色茶植物营养素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是有效的抑制Wnt信号通过诱导HBP 1转录抑制因子，这是一种抑制Wnt信号。抑制Wnt信号传导的分子基础将在基于细胞和动物的Wnt信号传导模型中进一步定义。在基于细胞的研究中，Wnt信号转导在乳腺细胞侵袭中的参与将得到解决。在EGCG机制的背景下，作为临床前研究，在MMTV-Wnt和异种移植小鼠模型中，将使用膳食补充EGCG来抑制定义的乳腺肿瘤发生。这些研究还可能为未来的临床研究定义新的生物标志物，并将HBP 1作为乳腺细胞侵袭性的可能调节因子。总之，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奠定有价值的基础。

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.