Project Summary Fisetin is a naturally-occurring phytochemical abundantly found in vegetables and fruits as the coloring agent. Preclinical studies have shown that fisetin offers anti-inflammatory and anti-oxidant benefits and protective effects against chronic diseases. Due to its significant benefits, consumption of fisetin as a dietary supplement is currently being studied in a clinical trial. Guided by our recent studies that showed fisetin significantly downregulates oncogenic signaling in breast cancer cells, we hypothesized that fisetin has chemopreventive effects against processes that are essential to breast cancer metastasis. Thus, using fisetin as a supplement may have preventive benefits against metastatic progression and significantly improve outcomes for patients. Because breast cancer metastasis occurs often very early and even before primary tumors are detected, preventing pro-metastatic processes is essential to improve outcomes for patients. We will test our hypothesis using our three-dimensional organotypic breast tumor model and a humanized mouse model of breast cancer, to study chemopreventive effects of fisetin on proliferation, epithelial-to-mesenchymal transition, and local invasion of cancer cells. Through phenotypic and mechanistic studies, we aim to demonstrate that fisetin supplementation will have benefits against breast tumor growth and frequencies of local and distant metastasis. In addition, our systematic studies in this project will help broaden investigations of dietary supplements as chemopreventive agents to block progression of breast cancer and other malignancies.