AGONIST-ANTAGONIST ACTIVITY OF ANTIESTROGENS IN THE HUMAN BREAST-CANCER CELL-LINE MCF-7 - AN HYPOTHESIS FOR THE INTERACTION WITH A SITE DISTINCT FROM THE ESTROGEN-BINDING SITE

Non-steroidal anti-estrogens exhibit an extremely complex pharmacology because of their estrogenic and anti-estrogenic effects in different species. Recently, we have reported evidence for an immunochemical dif ference in the estrogen receptor (ER) when it is occupied with anti-es trogens as compared to estrogens (Martin et al., 1988). In this study, we have compared immunoreactivity of MCF-7 cell estrogen receptor whe n bound to anti-estrogen versus estrogen. We show that the occupation of ER with antiproliferative concentrations of various anti-estrogens leads to the appearance of additional antigenic determinants for the H 222 monoclonal anti-estrogen receptor antibody. When performing ER imm unoassay after sedimentation of estrogen receptors on sucrose gradient s, we show that exposure of new epitopes induced by anti-estrogens can occur on a 4 s molecular form related to the 66 kDa monomeric estroge n receptor. Also, when ER are previously occupied by estradiol, the ad dition of low anti-estrogen concentrations, which are unable to displa ce estradiol from the estrogen receptor, leads to a significant increa se of H222 epitopes. Our results led us to propose a molecular model f or anti-estrogen-receptor interaction in which their dual agonist/anta gonist activity may be due to the occupation of distinct binding sites on the estrogen receptor.