Mechanisms of Ras Control of Mammary Tumor Properties in Transgenic Mice

Abstract : Expression of activated ras has been correlated with increased tumor resistance to apoptosis. We have previously demonstrated that tumors arising in MMTV-ras mice display low levels of spontaneous apoptosis and are resistant to the induction of apoptosis by chemotherapeutic agents. The goal of this project is to determine the role of two major ras effectors, raf1 and PI3K, in mediating tumor resistance to apoptosis. Transgenic mice expressing either constitutively activated or dominant negative forms of raf1 or PI3K are being created and characterized. Complementary cell culture studies are being performed to determine the effects of specific inhibitors of raf1 or PI3K on tumor cell growth and apoptosis. To date, we have generated two lines of mice expressing activated raf1 and three lines expressing dominant-negative raf1, and high levels of transgene expression have been detected in several lines. No tumors have been observed in these mice (up to a year of age) indicating that activated raf is insufficient to mediate the full tumorigenic effect of ras. Studies underway include: 1) interbreeding of these mice to various other lines of mice; 2) histological analysis and quantitation of raf signaling in mammary tissue from these mice; and construction of PI3K transgenes.