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Differences Between Estrogen- and Antiestrogen-Estrogen Receptor Complexes from Human Breast Tumors Identified with an Antibody Raised Against the Estrogen Receptor1

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Differences Between Estrogen- and Antiestrogen-Estrogen Receptor Complexes from Human Breast Tumors Identified with an Antibody Raised Against the Estrogen Receptor1 [CANCER RESEARCH 44,1012-1018, March 1984] Differences between Estrogen- and Antiestrogen-Estrogen Receptor Complexes from Human Breast Tumors Identified with an Antibody Raised against the Estrogen Receptor1 Anna C. Tate,2 Geoffrey L. Greene,3 Eugene R. DeSombre, Elwood V. Jensen,4 and V. Craig Jordan5 Department of Human Oncology, Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, Wisconsin 53792 [A. C. T., V. C. J.J, and Ben May Laboratory lor Cancer Research, University of Chicago, Chicago, Illinois 60637 [G. L G., E. R. D., E. V. J.] ABSTRACT INTRODUCTION Radiolabeled estrogens 17/3-[3H]estradiol and diethylstilbestrol The nonsteroidal antiestrogens are triphenylethylene deriva ([3H]DES) and the antiestrogen [3H]monohydroxytamoxifen tives that inhibit the effect of estrogens. This inhibition occurs in ([3H]MHT) all bind with high affinity to the extranuclear estrogen normal estrogen target tissue as well as in estrogen-dependent receptor (ER) from the MCF-7 human breast tumor cell line (K¿ malignant tissues (17) and has led to the widespread clinical use = 3 x 1(T10, 2 x 10.-10, and 0.63 x 1CT10M, respectively). A of the antiestrogen clomiphene for the treatment of infertility (12) polyclonal antibody raised in a goat to the calf nuclear ER and of the antiestrogen tamoxifen for the treatment of advanced selectively decreased the binding affinity and number of binding breast cancer (18). The subcellular mechanisms of action of the sites for 17j8-[3H]estradiol, but did not appear to affect these antiestrogens are, however, unclear (27). Both antiestrogens and binding parameters for [3H]MHT. In the presence of goat anti estrogens bind to the cytoplasmic ER6 and are translocated to body, the binding of the nonsteroidal estrogen DES was so the nucleus (3, 22), but antiestrogens inhibit or only partially perturbed that it was not possible to quantitate the decreased stimulate the nuclear events associated with estrogen action. number of binding sites or affinity of this compound as assessed Several possible subcellular sites of antiestrogen action have been proposed (17), and differences in the "activation" of the by Scatchard saturation analysis. These results were confirmed in human breast tumor cytosols extranuclear receptor (21, 24) and in the form of the nuclear by sucrose density gradient analysis. The binding of 17/3-[3H]- receptor (4) have been described. The presence of specific estradiol and [3H]DES to the ER was significantly reduced by "antiestrogen-binding sites" in mammalian tissue has also been preincubation with the polyclonal antibody, whereas the binding observed (28). At present, it is difficult to develop a single model of [3H]MHT was reduced only when the tumor cytosol was for antiestrogen action to incorporate all of these observations. preincubated with a very high concentration of antibody. At these [3H]Tamoxifen is available for studies of antiestrogens, but concentrations of antibody, the binding of 17/3-[3H]estradiol and this compound has relatively low binding affinity for the ER which [3H]DES to the receptor was prevented completely. In contrast, complicates the interpretation of biochemical studies. Recently, when the antibody was added to the tumor cytosol after the 3H- MHT, a metabolite of tamoxifen, has been synthesized in radio- ligand had bound to the receptor, the binding properties of all labeled form with high specific activity; this antiestrogen has an 3H-ligands were unaffected. The [3H]MHT-ER antibody complex affinity for the ER that is comparable to that of 170-estradiol (15) consistently sedimented as a higher-molecular-weight complex and has been used for studies both in vivo (14) and in vitro (1, on sucrose density gradients than did the corresponding estro- 29). The interactions of [3H]MHT with the cytosolic ER are genie complexes. qualitatively similar to those of 170-[3H]estradiol, although some The decrease in the affinity of estrogenic ligands can be differences have been observed (21). explained in part by an increase in the dissociation rate at 4°of Recently, a series of monoclonal and polyclonal antibodies these compounds from the ER. The dissociation rate of MHT raised to the ER have been developed that recognize different was unaffected by the goat antibody. antigenic determinants on the ER (9). These antibodies are, These results imply that there are important differences in the therefore, ideal probes to investigate steric or conformational binding of antiestrogen and estrogens to the tumor cytosol ER. changes on the ER that might be induced by antiestrogens but A ligand-binding model is proposed that may aid in the under not estrogens. Studies with monoclonal antibodies to the ER standing of antiestrogen action. have demonstrated no differences between 17/3-estradiol and MHT-estrogen receptor complexes from human breast tumors 1This study was funded in part by Grant P30-CA-14520 awarded to Wisconsin (29). Furthermore, a polyclonal antibody raised in the rabbit to Clinical Cancer Center and grants from I.C.I. Pic., Pharmaceuticals Division, Mac- the ER has been reported as able to distinguish between com clesfield, England, and an American Cancer Society Grant BC-86, at the University pounds with "high" and "low" affinity for the ER but not between of Chicago. 2 Recipient of a Fulbright-Hays Scholarship (1980/1981) and a University of estrogens and antiestrogens (5). Wisconsin Graduate School Scholarship in the Graduate Program of the McArdle In the present study, we have used a polyclonal antibody Laboratory for Cancer Research, University of Wisconsin. 3 Recipient of American Cancer Society Grant BC-86. raised in the goat which decreases the affinity and number of 4 Present address: Medical Director, Ludwig Institute for Cancer Research, 8001 binding sites for 17/3-[3H]estradiol in calf uterine cytosol (6). We Zurich, Switzerland. 5 To whom requests for reprints should be addressed, at Department of Human Oncology, Wisconsin Clinical Cancer Center, University of Wisconsin, 600 Highland * The abbreviations used are: ER, estrogen receptor; MHT, 1-[4-<2-dimethylami- Avenue, Madison, Wl 53792. Recipient of a grant from I.C.I., Pte., Macdesfield, noethoxy)phenyl]-1 -(4-hydroxyphenyl)-2-phenylbut-1 -ene; DES. diethylstilbestrol; England. DCC, dextran-coated charcoal; TEM, Tris (10 mM), EDTA (1.5 ITIM),and monothio- Received May 9,1983; accepted December 2, 1983. glycerol (5 mw), pH 7.4. 1012 CANCER RESEARCH VOL. 44 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1984 American Association for Cancer Research. Human Breast Tumor ERs have confirmed that this antibody produces a similar effect on fluid (Amersham) to determine the level of radioactivity. Specific binding the binding of 17/3-[3H]estradiolin the MCF-7 human breast was obtained by subtracting nonspecific binding from total bound radio tumor cytosol that is known to contain ER (11). We have ex activity. tended these studies by comparing and contrasting the effect of Determination of Dissociation Rate in the Presence of Goat Anti the goat antibody on the binding of [3H]DES and [3H]MHT to body. Cytosols from MCF-7 cells were preincubated with goat antibody (at approximately 50 pg antibody/pmol ER) for 2 hr at 4°.The cytosol human breast tumor ER. The effect of the antibody appears to was then transferred onto 10 *il 17/J-[3H]estradiol (5 nM), [3H]DES (5 nM), be selective for estrogenic compounds and indicates that there or [3H]MHT (10 nM) in ethanol and incubated for 2 hr at 4°;double the are different steric or conformational changes in the cytosol concentration of [3H]MHT as 17/3-[3H]estradiol was used, since only the receptor when complexed to antiestrogens compared with estro frans isomer (50% mixture) binds under these conditions (13). Nonspe gens. These findings form the basis for a proposed model of cific binding was determined in parallel incubations containing a 100-fold antiestrogen and estrogen binding to the ER. excess of cold ligand. The cytosol was then transferred onto DCC pellets formed from 1 ml of DCC suspension, and the tubes were agitated and incubated for 20 min at 4°and then centrifuged at 1000 x g for 10 min. MATERIALS AND METHODS The cytosols were transferred onto 10 n\ of ethanol or 10 n\ of a 1000- fold excess of the appropriate ligand to promote dissociation of bound 17/í-[6,7-3H]Estradiol (60 Ci/mmol in tolueneiethanol, 9:1) was ob ligand (23). At the time points indicated, bound and free ligand were tained from the Radiochemical Centre, Amersham, England, and was separated by removing 200-^1 aliquots of cytosol in duplicate onto 500 repurified on an LH-20 column by elution with 85% toluene: 15% meth- n\ of DCC suspension. The tubes were agitated for 10 min at 4°and anol. [3H]DES (112 Ci/mmol) in toluene was obtained from Amersham, then centrifuged at 1000 x g for 10 min to remove charcoal. Aliquots and its purity was checked by thin-layer chromatography developed with (100 fi\) were removed from each tube and transferred into 10 ml aqueous chloroform:ethyl acetate (85:15). Approximately 25% of the [3H]DES was the c/'s geometric isomer, and this percentage did not change appreciably counting scintillant scintillation fluid, and the radioactivity was determined in a Tracor analytical liquid scintillation counter. Specific binding was over a 2-week period. No attempt was made to separate the c/s and obtained by subtracting nonspecific binding from total bound radioactiv frans geometric isomers on this thin-layer chromatography system, since ity. the eluant was found to have significantly diminished binding capacity The inactivation of 17/3-[3H]estradiol-ER complex, during the course for the receptor. The [3H]DES was used as an approximately 75:25 of these assays, was assayed without the addition of a 1000-fold excess mixture of frans and c/s geometric isomers.
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