Nuclear translocation and interactions of the estrogen receptor in uterus and mammary tumors

The mechanism of the nuclear translocation of the estrogen receptor (ER) and the nature of the acceptor sites interacting with the ER-estrogen complex are unknown. We report here results of our laboratory aiming to solve the following problems in the uterus and mammary tumors systems. 1. Mechanism of the activation of the cytosol ER leading to its nuclear translocation: The nuclear translocation of ER is triggered by all ligands tested thus far either agonist or antagonist. From the physico chemical characteristics of the nuclear ER extracted by micrococcal nuclease digestion, we propose that the mechanism of the activation of ER is not the Ca 2+-dependent proteolysis of the receptor and might be a simple conformational change. 2. Is DN A a biological acceptor of ER? our results are in agreement with, but do not prove such an hypothesis, (a) The native nuclear ER is extracted after micrococcal nuclease digestion in a form which is still able to bind DNA. (b) Intercalating drugs inhibit 50% of translocation of the ER to the nucleus, (c) Preliminary experiments with 5-bromodeoxyuridine aiming to cross-link in vino the nuclear ER to DNA in MCF 7 cells are also consistent with this hypothesis. 3. Acceptor and Effector sites: The relationship between the nuclear components interacting with the receptor and possibly responsible for its nuclear retention (acceptor sites) and the nuclear components interacting with the receptors to give a response (effector sites) is discussed on the basis of results obtained in estrogen responsive and unresponsive systems. Results obtained in independent mammary tumors of C3H mice and dimethylbenzanthracene treated rats, and with the antiestrogens in MCF, cells strongly suggest that the nuclear translocation step is required but not sufficient to induce the estrogenic response.