The Role of the Prohibitin Gene in Apoptosis of Breast Cancer Cells

Prohibitin, a potential tumor suppressor protein, was originally identified by its ability to induce G1/S arrest in human fibroblasts. Mutations in the prohibitin gene were subsequently found in sporadic breast tumors. Our experiments in B cells and breast cancer cells suggest that prohibitin protects against apoptosis induced by camptothecin, a topoisomerase I inhibitor. A human B cell line (Ramos) stably overexpressing prohibitin and treated with camptothecin exhibits 50% less apoptosis compared to the parental cell line. BT 549 breast cancer cells, which express high levels of endogenous prohibitin, exhibit 20% less death from camptothecin than ZR 751 cells, which have low levels. E2F transcriptional activity increases in response to camptothecin, but this increase is attenuated in cells overexpressing prohibitin. Moreover, we find that prohibitin and p53 associate in vitro and co-localize in the breast cancer cell lines MCF7 and T47D. Functionally, prohibitin may activate p53 mediated transcription and augment p53 binding to a target promoter. Further, prohibitin was specifically exported from the nucleus of breast cancer cells, but not normal cells.. The role of this in cellular apoptosis is being evaluated. Our studies are elucidating the mechanisms whereby prohibitin affects the chemotherapeutic response and may help in directing therapeutic strategies for breast cancer treatment. The original document contains color images.