Grant: Project Grant

The 10-year survival rate for women with localized breast cancer is 75%. However, patients with metastatic disease face a dismal survival rate of only 2%. Metastatic breast cancers contain high numbers of breast cancer stem cells, and it is believed that these cells are at the root of therapy resistance and disease recurrence. The proposed work strives to isolate and eradicate this important population. Our preliminary data strongly suggest that inhibition of mTOR activity, leading to dephosphorylation of 4EBP, results in an increased expression of Nodal concomitant with the induction breast cancer stem cell-phenotypes. The proposed work will follow up on this exciting finding, to determine if mTOR inhibition, or other drugs that inhibit protein production, may inadvertently select for residual disease. MTOR inhibitors are being used in clinical trials for the treatment of breast cancer. While positive results have emerged, resistance still ensues, and single-agent mTOR inhibitors have had limited clinical activity. The failure of these approaches may be due to the survival and/or selection of breast cancer stem cells. Hence, targeting Nodal may improve outcomes in patients treated with mTOR inhibitors. This work is innovative as the role of Nodal in breast cancer stem cells has not yet been established. Moreover, the possibility that mTOR inhibitors and other chemotherapies may induce and/or select for cancer stem cells is provocative.