Investigation of the Oncogenic Role of Prohibitin in Breast Cancer Progression

Cancer is the major cause of death worldwide, and breast cancer is the second leading cause of cancer death among women in the United States. In 2011, more than 280 thousands women are diagnosed with breast cancer and nearly 40 thousands patients die of the disease. In the previous study, we revealed that prohibitin (PHB) is overexpressed in patients with breast carcinoma and exhibited particular plasma membrane localization in tumor tissues. PHB plays various roles in inhibiting tumor growth and cell proliferation, inducing apoptosis and anti-senescence. Several studies indicated that the level of serum PHB is higher in cancer patients, and overexpression of PHB could neutralize the efficacy of apoptosis induced drugs in clinical suggesting PHB might demonstrate an anti-apoptosis function and cause drug resistance. Interestingly, we demonstrated that the subcellular localization of PHB was associated with tumor progression, suggesting the oncogenic role of PHB in breast cancer. Inhibition of PHB by its inhibitor rocaglamide significantly decreased the cell viability, caused cell cycle arrest at G2/M phase, reduced migratory ability, and induced apoptosis. Systems biology is a biology-based inter-disciplinary, emphasizing a systematic view to understand the behaviors in biological organisms. To improve the understanding of the role of PHB in breast cancer cells, the major objective of this proposal is to apply systems biology approaches to elucidate the PHB-mediated pathways as a foundation for improving breast cancer therapy. The specific aims are 1. To study effects of surface localized PHB on tumor growth, metastasis, and invasion in breast cancer cells. (Year 1) 2. To elucidate the protein-protein interaction networks of subcellular localized PHB-mediated breast cancer progression. (Year 1~2) 3. To identify the protein interaction domain of PHB that modulating tumor progression. (Year 2~3) 4. To measure the inhibitory effects on tumor behaviors by agents targeting PHB and disturbing its protein-protein interaction in vitro and in vivo. (Year 2~3)