Dietary Flavonoids Targeting Triple Negative Breast Cancer

OBJECTIVES: Breast cancer remains the leading cause of malignancy-related death in females and continues to increase in prevalence worldwide. The lack of therapies for triple-negative breast cancer (TNBC) continues to be a challenge, owing to its highly metastatic and aggressive nature. Dietary flavonoids, found in fruits and vegetables, are attracting great interest in the prevention and treatment of TNBC due to their anti-carcinogenic, anti-oxidative, and anti-inflammatory properties. The goal of our project was to evaluate the structure-activity relationship and the mechanism by which flavonoids affect TNBC tumor growth and metastasis. METHODS: We investigated the effects of structurally related flavonoids on the migratory nature of human MDA-MB 231 TNBC cells by using a wound healing migration assay. To model the effects of flavonoids in tumor heterogeneity in vivo, 3-dimensional culture organoids from TNBC derived xenograft tumors were established. Small interfering RNA (siRNA) transfection of apigenin target heterogeneous nuclear ribonucleoproteins A2 (hnRNPA2), an oncogene overexpressed in cancer cells that leads to abnormal mRNA splicing, were employed to investigate how hnRNPA2 effects alternative mRNA splicing activity. RESULTS: We observed that the natural flavonoids apigenin and kaempferol inhibited migration in a dose-response manner. Conversely, the presence of a glucoside and/or the lack of double bonds within the flavonoid structure as in the case of apigenin-7-glucoside and flavanones exhibited no significant anti-metastatic effects. Analysis of hnRNPA2 knockdown revealed key insights into the interaction of apigenin with hnRNPA2 to regulate migratory behaviors. CONCLUSIONS: These novel insights showcase dietary flavonoids as practical functional foods that can benefit clinical applications in TNBC cancer prevention and treatment of tumor metastases and growth. FUNDING SOURCES: Through grants from United States Department of Agriculture, National Science Foundation, and MSU awarded to Dr. Andrea I. Doseff, NIH-T32 Plant Biotechnology for Health and Sustainability Fellowship to Meenakshi Sudhakaran, and the REPID Program funded by National Institute of Health and directed by Dr. Elahé Crockett.