Biological Roles of Map K Cascades in Breast Cancer Cells

Abstract : The purpose of this project is to better understand the signal transduction pathways that mediate growth inhibition of breast cancer cells. In fibroblasts, the classical MAPK pathway (Ras/Raf-1/MEK/ERK) mediates the proliferative response by growth factors; while the novel MAPK pathway (Ras/Rac/MEKK1/JNKK1/JNK) may be involved in growth inhibition. A growth factor receptor ErbB-2, which is a critical regulator of the growth and differentiation of breast cells, is overexpressed in 25% of human mammary tumors. Interestingly, its ligand NDF (neu differentiation factor) can either induce the proliferation or differentiation of breast cancer cells. Using mammary carcinoma cells, which proliferate or differentiate upon NDF addition, the respective roles of the two MAPK cascades in controlling cell growth and differentiation are examined. As demonstrated in this report, both the JNK and the ERK cascades are activated at similar kinetics in the differentiative AU565 and the proliferative SKBR3 cells. However, JNK is marginally activated in the proliferative MCF7 cells and not activated in the differentiative MDAMB453 cells. In contrast, ERK is strongly activated by NDF in MCF7 cells, while it is only moderately activated in MDAMB453 cells. Thus, no correlation has been found between the activation profile of the JNK and ERK cascades and the growth responses of the above four mammary carcinoma cells.