Novel Synthetic Antiestrogens That Block Nuclear Estrogen Receptor Function Through Plasma Membrane Localization

摘要

Hormonally responsive breast cancers that respond favorably to antiestrogens such as tamoxifen often become resistant to this treatment. We are working to identify novel antiestrogens that promote plasma membrane localization of estrogen receptors (ERs). Thus far, we have not successfully recruited ERs to plasma membranes. To probe the failure of the ER recruitment system we studied the ability of membrane-anchored ligands to recruit other intracellulary-expressed proteins that might provide a simpler model system of the ER. Studies of a cholesterylamine-biotin chimera led to the discovery that this compound promotes streptavidin SA, expressed in Jurkat lymphocytes, fused to Green Fluorescent Protein (GEP) and Apo-l recruitment to the plasma membrane. This biotin - SA system provides a great model for further studies of hER membrane recruitment. Because such compounds 'dimerize' SA with the plasma membrane, we were interested in compounds that could dimerize SA with the estrogen receptor. Toward that end, we developed a novel chemical inducer of dimerization comprising beta-estradiol linked to biotin. This compound potently dimerizes streptavidin and the estrogen receptor in the nucleus of yeast. This result sheds more light on methods for manipulating the estrogen receptor in living cells.