Breast cancer is the most common malignancy in women and the leading cause of death in women over 40 to 55 years old. Despite the advances and improvements in early detection and treatment, the incidence of this disease has increased and the mortality is unaltered. A clear understanding at the molecular and cellular levels of factors that regulate the growth and differentiation of breast cancer cells will provide insights into this complicated disease and may open new avenues for developing alternative treatments. Oncostatin M (OM), a cytokine produced by activated T-lymphocytes and macrophages has been shown to inhibit the growth of a number of breast cancer cell lines and primary breast tumor cells isolated from solid tumors or malignant effusions. The strong growth inhibitory and differentiative activities of OM on breast cancer cells and its unique source of production by activated mononuclear leukocytes suggest that this cytokine might be involved in a host defense to fight tumor progression in vivo. However, currently, little is known about the underlying principal of OM s antigrowth activity on breast cancer cells. The overall objectives of this proposal are to elucidate the molecular mechanisms how the OM antigrowth and differentiation signal is transduced from the membrane to the nucleus.
The specific aims of this proposal are threefold: (1) determine whether MAP kinase ERK plays a pivotal role in OM-induced growth inhibition and differentiation of breast cancer cells. Dominant negative mutants will be utilized to inhibit the activities of the endogenous proteins in the MAP kinase pathway and the STAT pathway, (2) identify ERK interacting proteins that are involved in breast cancer cell growth and differentiation by expression screening with activated ERK1 and [gamma-32P]ATP, and (3) identify the cis-acting elements and the trans-acting factors that mediate the suppressive effect of OM on c-myc transcription in breast cancer cells. These studies will provide important insights into the molecular mechanisms responsible for the actions of OM on the control of the growth and differentiation of breast cancer cells.
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