This proposal is designed to study the mechanisms by which triphenylethylene antiestrogens inhibit the growth of MCF-7 cells as well as inhibiting various estrogen induced responses. The availability of antiestrogen- resistant MCF-7 variants will allow us to test our hypothesis that the lack of growth inhibition by antiestrogens in these variant cell lines is correlated with the loss of specific non-histone chromosomal protein(s) or alterations in chromosomal protein(s) which may constitute a component of chromatin acceptor site(s) in antiestrogen-sensitive cells. We will use the antiestrogen H1285 which we have shown has high affinity for the estrogen receptor in MCF-7 cells. We will study the physicochemical properties of the cytosol and nuclear estrogen receptor when bound by estrogen versus antiestrogen. Emphasis will be on preparing purified receptor as both monomers and dimers and studying the binding of these receptor forms to reconstituted chromatin acceptor sites. These experiments will allow us to test the hypothesis that antiestrogens stabilize the receptor in the dimeric form, and thus alter receptor interaction with certain chromatin acceptor sites which may result in differing biological responses when compared with estogens. Various acceptor proteins will be partially purified and reconstituted to DNA in order to study these highly hydrophobic non-histone chromosomal proteins which, in association with DNA, impart high affinity and specificity to the binding of the receptor complexes. The results of such studies will indicate whether antiestrogen-receptor complexes bind to a unique acceptor site in MCF-7 cells which might be involved in the growth- inhibiting action of antiestrogens in these breast tumor cells.
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