Dominant-Active Alleles of Rbi as Universal Tumor Suppressors of Mammary Cacinoma

摘要

The tumor suppressor Rb is thought to be genetically or functionally inactivated in virtually all human cancers including, breast cancer. The Rb protein is negatively regulated by cyclin dependent kinases. The goal of this project is to generate transgenic mice expressing phosphorylation-resistant Rb in the mammary gland and test whether these dominant active alleles of Rb can prevent breast cancer induced by distinct oncogenic pathways in mouse models. In the past year, we have constructed the transgenic plasmids and established 23 MMTV-Rb-delta-K transgenic lines. RT-PCR analysis revealed that some of the transgenic lines expressed various levels of the transgene. We are currently testing the expression of the transgenes in the rest of the lines and study the effect of the transgenes on development of the mammary gland. We will next mate the MMTV-Rb-delta-K transgenic mice with MMTV-myc, MMTV-cyclinD1 and MMTV-neu in order to test whether expression of unphosphorylated Rb can suppress breast cancer in mouse models. If our studies indicate that Rb can prevent or reverse neoplastic growth, future studies will focus on designing strategies to activate the Rb pathway as preventive or therapeutic treatments for breast cancer.