Our research centers on (1) steroid receptors as mediators of growth and differentiation, (2) selective estrogen receptor-modulators (SERMS), and (3)steroid receptor-directed imaging and therapy of cancer. We are interested in the process by which breast cancers escape the receptor-mediated control of growth and are comparing differences between two estrogen receptor positive breast cancer cell sublines of MCF-7 human breast cancer cells, one in which estrogen causes increased cell proliferation, the other which grows at the same, more rapid rate in the presence and absence of physiologic concentrations of estradiol. It is now recognized that both steroidal and non-steroidal antiestrogens can cause breast cancer regression, but that often antiestrogens that are effective for therapy of breast cancer therapy can have undesirable effects on other tissues. New SERMs that can be used for breast cancer without increasing the risk of endometrial cancer and for postmenopausal estrogen replacement therapy without undesirable side effects are being sought. We are collaborating in a multi-institutional study to identify such new SERMs, using novel synthetic methods, in vitro assays of competitive binding for estrogen receptors α and β, in vitro and in vivo assays of activity against breast cancer, and in vivo assessment of effects on uterus, bone and serum cholesterol. The results of the in vitro and in vivo assays are to be compared with molecular modeling and 3D structure of binding of the ligands to the estrogen receptor.

With regard to steroid-directed imaging and therapy of cancer we have prepared halogenated, steroid receptor-binding ligands which contain either iodine-123 (13h half-life) or bromine-80m (4.4h half-life), two Auger electron-emitting nuclides, the latter prepared in a cyclotron by proton bombardment of a selenium-80 target. We recently reported an estrogen receptor-mediated, dose-dependent radiotoxicity of Auger electron-emitting, I-123-labeled estrogens in cells in vitro, and the relationship between Auger electron-induced DNA breaks, chromosome aberrations and cell radiotoxicity. We are currently developing an animal model to test this new approach to therapy. At the same time we are exploring the basic radiobiology and quantitative characteristics of such Auger electron-mediated cytotoxicity. These studies in model systems include radiolysis via Auger electron-emitting estrogen complexes with estrogen receptor binding to estrogen response elements associated with estrogen-responsive genes but contained in short lengths of double strand DNA, longer DNA in plasmids or present in chromosomes after permanent transfection to estrogen receptor containing cells. The studies should clarify the molecular dimensions of Auger electron damage, and may provide insight into the 3D structure of the complex of estrogen receptor with estrogen response element DNA.