Nuclear Acceptor Sites for the Mammalian Estrogen Receptor: Effects of Antiestrogens

Abstract

Estrogenic steroid hormones interact with target tissues through their binding to specific receptor proteins (1–3). Triphenylethylene derivatives inhibit several estrogen-stimulated responses, and are thus termed anti-estrogens (4–6). Triphenylethylene antiestrogens have been used effectively in the treatment of hormone-dependent cancers. MCF-7, a well established human breast cancer cell line, has been a useful tool for steroid receptor studies as these cells contain high levels of estrogen and progesterone receptors, and cell growth is inhibited markedly by antiestrogens in the absence or presence of estrogens (7–12). Current studies of antiestrogen action utilize high affinity triphenylethylene derivatives which allow a more accurate assessment of the physicochemical characteristics of receptor complexes (13–15). Although physicochemical differences in the estrogen receptor bound by estrogen versus antiestrogen have been reported by our laboratory as well as by others (16–20), it is not clear how these receptor complexes interact with nuclear binding sites which have been proposed to involve various domains such as DNA sequences, chromatin, nucleoacidic proteins and nuclear matrix (21–25). Thus, the cellular mechanisms whereby these triphenylethylene compounds provoke agonist, antagonist, and unique responses is still not clear. Antiestrogens act as mixed agonists/antagonists both in vivo and in vitro.