Grant: Master's Award: Canada Graduate Research Scholarships - Master's program

Breast cancer affects 1 in 8 women in Canada, with triple-negative breast cancer (TNBC) remaining one of the most difficult subtypes to treat due to the lack of hormone and HER2-targeted options. New therapeutic strategies are needed. Salvia miltiorrhiza, a plant used in Chinese medicine, has shown benefits in cardiovascular disease and contains natural products with reported anticancer activity. While tanshinone IIA has been studied, many related compounds remain untested. I have synthesized a panel of 8 salvia miltiorrhiza natural products. From these, tanshinone IIA anhydride and normiltirone produce a clear hormetic response in MDA-MB-231 TNBC cells based on MTT viability assays. Hormesis occurs when low concentrations stimulate cell activity while higher concentrations inhibit it. The remaining natural products do not induce hormesis but show distinct cytotoxicity patterns between TNBC and normal mammary cells. The mechanisms that distinguish hormetic from non-hormetic responses are unknown. This project will investigate the signaling pathways involved in hormesis caused by tanshinone IIA anhydride and normiltirone. Stress-response pathways such as MAPK/ERK, JNK and Akt, along with reactive oxygen species (ROS), may contribute to this effect. Using IC50 values I have established, I will test whether different concentrations alter ROS levels through fluorescence-based assays and measure activation of ERK, JNK and Akt by western blot. I will also determine whether non-hormetic compounds activate these pathways in a similar or distinct manner. All experiments will include three biological replicates.This work will clarify what drives hormesis in TNBC cells and provide initial mechanisms of action for several previously unexplored salvia miltiorrhiza natural products