The dual function steroid receptor coactivator/ubiquitin protein-ligase integrator E6-AP is overexpressed in mouse mammary tumorigenesis

Steroid receptor coactivator and corepressor proteins are important mediato rs of steroid receptor function. Changes in the expression or activity of t hese limiting cofactors can contribute to the etiology of steroidal cancers . Using a mouse mammary model of multistage tumorigenesis we have examined whether the expression of select steroid receptor coactivators is altered. The 10 kb transcript of the novel dual function steroid receptor coactivato r/ubiquitin protein-ligase integrator E6-AP is overexpressed 2.5-4.5 fold i n the mammary tumors but not in the precursor steps of tumorigenesis; that is, immortal ductal and alveolar hyperplastic outgrowths. The over expressi on is striking because the 10 kb transcript is expressed to variable levels in other wild type tissues like the uterus, ovary, testis, kidney and brai n but is undetectable in normal virgin mammary gland and the prostate gland . The E6-AP overexpression in the mammary tumors is substantiated by wester n blot analysis and immunohistochemical analysis. Absence of ER and PR in t hese tumors in the presence of high levels of E6-AP could contribute to ste roid receptor-independent function and tumorigenesis. There is no obvious c orrelation between p53 (a well-characterized substrate of E6-AP) status (wt vs. mutant) and levels of E6-AP in the mouse mammary tumors.