MITOGEN ACTIVATED PROTEIN KINASES AND BREAST CANCER

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Breast cancer etiology and pathogenesis remain unclear, but several observations suggest a role for the mitogen activated protein (MAP) kinase cascade in breast cancer progression. The aim of our study is to understand the mechanism by which breast cancer cells grow and enhance invasion into surrounding tissues a characteristic feature of malignant tumors. It was previously shown that in breast cancer, most growth and oncogenic signals that leads to tyrosine phosphorylation activates MAPK cascade. The activated MAPK (ERK1 and ERK2) translocates from cytoplasm to the nucleus where it regulates nuclear proteins and transcriptional factors such as AP-1 which regulate proteases such as urokinase (uPA) and matrix metalloproteinase (MMP-9) that are shown to be involved in matrix degradation. Our preliminary studies using breast cancer cells suggest that down regulation of MAPK activity disrupt cell proliferation, motility and invasion phenotype, suggesting that activation of MAPK cascade, might be part of both normal cellular events and oncogenic transformation. This proposal is based on the hypothesis that overexpression and/or consistent activation of MAPK in breast epithelial cells results in increased protease induction and cell motility, leading to the acquisition of an invasive phenotype in breast and other tumor. We have three objectives: (1) To study the effect of MAPK (ERK1) overexpression and/or activation on cell transformation in breast epithelial cells. (2) To study the role of activated MAPK in the induction of tumorigenicity and metastasis. (3) To determine the importance of the MAPK in the induction of benign proliferative and malignant changes in mammary gland using transgenic mice. These studies will provide important new information on the mechanism of breast cancer development and progression. The long term goal is the identification of molecular events underlying tumor progression that are potential targets for the development of rational therapeutic agents.