Role of MEKK3 Signaling Pathway in the Resistance of Breast Cancer Cells to TNF-(alpha)-Mediated Apoptosis

摘要

With the support from the DOD Breast Cancer Research Program, the research conducted in the past three years has tested the hypothesis that the NF-kB activation and MAPK activation by MEKK3 plays a critical role in breast cancer growth and survival in response to anti-cancer drugs and to cytokine treatment. We used dominant interfering forms of MEKK3 mutant to examine how perturbation of the MEKK3 pathway may affect breast cancer growth, survival and responses to cytokines. We found that MEKK3 is essential for cytokine induced NF-kB and MAPK activation in fibroblasts. We also developed small interference (si) RNA strategy to inhibit MEKK3 expression in breast cancer cells and used MEKK3 specific antibodies to examine the MEKK3 expression and activation in normal mammary gland cells and in breast cancer cells. Our studies revealed that MEKK3 signaling pathway may be a key regulator for breast cancer cell growth, survival and migration. Our studies also suggest that too little MEKK3 activity may cause cancer growth retardation and affect its migration potential, while too much activity may lead to cell death. These studies will allow us to reveal novel targets and to develop new strategies to treat and prevent breast cancer.