Role of Cortactin in Cell Growth and Differentiation

Chromosome 11ql3 is amplified in 13% of primary breast cancers and is indicative of a poor prognosis (1). The region amplified includes the cyclin Dl gene, hst-l, int-2, and emsl (cortactin); however, only cyclin Dl, a cell cycle regulator, and cortactin, a cytoskeletal protein, are overexpressed. Several studies have shown increased levels of these proteins in different breast cancer cell lines and their amplification is associated with a more invasive phenotype; however whether or not these proteins are directly contributing to the enhanced tumorigenic potential has not been clearly addressed (2). While the function of cyclin Dl is fairly well understood very little is known about the function of cortactin overexpression in mammary tumorigenesis. The goals of this proposal are to 1) understand the function of cortactin in normal cell growth and differentiation; 2) determine the consequences of cortactin overexpression in mammary epithelial cells; and 3) identify% cellular targets of cortactin. These goals will be achieved using genetic, biochemical, and cell biological approaches including generation of mice carrying a targeted disruption in the cortactin gene, derivation of mammary epithelial cells overexpressing wild type and mutant cortactin, and analysis of a two-hybrid screen using full length cortactin.