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. ? ?
