Whether p21ras plays a role in regulating the transformed phenotype of breast cancer cells is not clear. Mutations in the ras gene are almost never detected in breast cancer. On the other hand, activated tyrosine kinases play an important role in breast cancer pathogenesis and, in other systems, exert some of their effects by activating wild type p2lras. If this is so in breast cancer, inhibition of p2lras function with drugs such as farnesyl transferase inhibitors (FTIs) could be an important therapeutic strategy. We have shown that polypeptide growth factors activate the ras-regulated signal transduction pathway in breast cancer cells and that introduction of the Nl7-ras dominant negative into a breast cancer cell line does not alter proliferation but reverses transformation. We conclude that activation of wild type p2lras is necessary for maintenance of transformation in at least some breast cancer cells. Furthermore, we have shown that these tumor cell lines are sensitive to farnesylation inhibitors. We propose in this grant to use dominant negative ras vectors to determine the role ras-regulated pathways play in the biology of breast cancer. We further plan to investigate the mechanism by which FTIs suppress breast cancer cell growth, to explore whether they work by inhibiting ras processing or whether they have other targets as well, and to determine mechanisms underlying cellular resistance to these drugs. The main goals of the work are to develop the possibility of using FTIs clinically and to use our knowledge of signal transduction pathways to design new therapies that combine such inhibitors with traditional chemohormonal therapy.
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