The Role of N-CoR During Normal Mammary Gland Development

Abstract

Abstract : Recently, coactivator and corepressor complexes required for function of estrogen receptor (ER), and other nuclear receptors, have been identified, with critical implications for aspects of etiology and therapy of breast cancer. Studies of the mechanisms of estrogen receptor and tamoxifen actions in ours and in other laboratories have permitted new insights to breast cancer diagnosis and therapy. Previous results have shown that the most widely utilized anti-estrogen in the treatment of breast cancer, Tamoxifen causes ER to associate with the N-CoR corepressor complex, and that this association is required for its anti-estrogen effects. Inhibition of N-CoR binding actually causes a in tamoxifen function from inhibition to activation. Thus, we hypothesize that resistance in ER- positive tumors is frequently based on alterations in levels or on post-transcriptional modifications in N-CoR, or other members of the corepressor complex that will abolish recruitment of the corepressor complex to the receptor resulting in a switch from antagonist to agonist actions. I propose to test this hypothesis using a genetic approach. My experiments will determine the levels of expression of N-CoR protein and mRNA during normal mammary gland development, as well as to determine the cellular localization patter of N-CoR with respect to ER during development. Next, two genetic approaches will be utilized to test the biological role of N-CoR during normal development. First, analysis of mammary glands of mice in which N-CoR has been deleted will be performed over the course of normal mouse mammary development. Tissues from N-CoR gene-deleted mice will be treated with the carcinogen DMBA to determine if deletion or expression of N-CoR enhances or suppresses mammary tumors.