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Characteristics of Binding to Estrogen, Androgen, Progestin, and Glucocorticoid Receptors in 7,12-Dimethylbenz(A)

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Characteristics of Binding to Estrogen, Androgen, Progestin, and Glucocorticoid Receptors in 7,12-Dimethylbenz(A) [CANCER RESEARCH 40. 1612-1622, May 1980] 0008-5472/80/0040-OOOOS02.00 Characteristics of Binding to Estrogen, Androgen, Progestin, and Glucocorticoid Receptors in 7,12-Dimethylbenz(a)anthracene- induced Mammary Tumors and Their Hormonal Control1 Jacques Asselin,2 RéjeanMelançon,Gilbert Moachon, and Alain Bélanger Laboratory of Molecular Endocrinology, Le Centre Hospitalier de I UniversitéLaval, Quebec G1V4G2, Quebec. Canada ABSTRACT induced mammary tumors in the rat. Moreover, as revealed by hypophysectomy, adrenalectomy, and ovariectomy, the levels In order to perform simultaneous measurement of binding of of the progesterone and glucocorticoid receptors are under four classes of steroids and facilitate study of their mechanism different hormonal control. of action in 7,12-dimethylbenz(a)anthracene-induced mam mary tumors in the rat, we have investigated in detail the binding characteristics of 17/3-[2,4,6,7,16,17-3H]estradiol INTRODUCTION (17/8-[3H]estradiol), 17,21 -[6,7-3H]dimethyl-19-norpregna- 4,9-diene-3,20-dione ([3H]R5020), [3H]dexamethasone (DEX), Treatment of human breast cancer by endocrine manipula and 5a-[3H]dihydrotestosterone (DHT) in cytosol prepared from tion has shown that a certain proportion of these tumors are hormone dependent. This is supported by the presence of these tumors. Following assessment of optimal buffer compo steroid and peptide receptors in these tumors. In fact, estrogen sition, separation of bound and free steroids was achieved with (16, 23, 27, 41, 45), progesterone (38, 41, 45), and androgen dextran-coated charcoal, protamine sulfate, or hydroxylapatite. (31, 39) receptors have been reported in cytosol prepared Using the same buffer and the optimal method of separation from human breast cancer biopsies. Moreover, estrogen, pro for each tracer, we have found that the time course of binding gesterone, androgen, and glucocorticoid receptors have been of each labeled steroid was fast, the slowest rate of association demonstrated in the MCF-7 human breast cancer cell line (18). being obtained with [3H]DEX (t = 100 to 150 min) at 4°. In Binding of insulin, prolactin, and growth hormone has also addition, the level of specific binding of each tracer was stable for a period of at least 21 hr at 4°but decreased markedly at been described in human mammary carcinoma (17). Hormone-dependent mammary tumors developed in the rat 23°(except with 17/?-[3H]estradiol). Complete exchange of the are widely used as models of human breast cancer. Thus, the tracer from the binding component was achieved at 4° for growth and development of a large proportion of mammary [3H]R5020 and at 23°for 17/S-[3H]estradiol. Although [3H]DEX tumors induced in the rat by DMBA3 (21) are markedly influ dissociated from its binding component at 4°, the receptor enced by the endocrine status of the animal. Investigations at complex was unstable during long-term incubations necessary the molecular level have shown the presence of prolactin- (25, to achieve complete exchange. No significant exchange of 46), insulin- (25), and growth hormone- (25) binding compo [3H]DHT binding occurred at 4°.Using six increasing concen nents in this experimental mammary tumor. Moreover, estro trations of a large series of unlabeled steroids, each tracer gen- (23, 33), progesterone- (4, 19), glucocorticoid- (13), and showed a high degree of binding specificity. Sucrose gradient more recently androgen- (22) binding components have been analysis performed in low-ionic-strength buffer revealed spe found in the same tissue. The finding of specific hormone- cific and protamine sulfate-precipitable steroid-binding com binding components combined with the effect of hormone ponents migrating in the 8 to 9S area for 17/?-[3H]estradiol, 7S therapy on the growth and development of the DMBA-induced and 4 to 5S for [3H]R5020, and 7 to 8S for [3H]DEX and mammary tumor are good indicators that this neoplastic tissue [3H]DHT. Sucrose gradient analysis in a high-ionic-strength represents a good model of human hormone-dependent breast buffer (0.4 M KCI) gave only one labeled area (3 to 5S) for each cancer. tracer. Scatchard analysis revealed Kd's of 0.14 nw for 17/8- In order to further understand the mechanisms of steroid [3H]estradiol, 2.9 nM for [3H]R5020, 13 nM for [3H]DEX, and action in the development of this mammary tumor, it appears 0.45 nM for [3H]DHT binding. important to make a detailed comparison of the characteristics In a second series of experiments, while adrenalectomy had of steroid binding, as well as of the hormonal factors controlling no effect on the binding of any of the four classes of steroids, steroid-binding levels in the normal mammary tissue and the 17/8-[3H]estradiol, [3H]R5020, and [3H]DHT binding levels were DMBA-induced mammary tumors. Although the presence of decreased in 7,12-dimethylbenz(a)anthracene-induced mam the 4 types of steroid-binding components has been reported mary tumors after ovariectomy plus adrenalectomy or hypo- in cytosol from DMBA-induced mammary tumors, no detailed physectomy, while the binding of [3H]DEX remained un investigation of the binding properties of the different classes changed. The present data describe the optimal conditions for simul 3 The abbreviations used are: DMBA, 7,12-dimethylbenz(a)anthracene; taneous and specific measurement of binding of four classes R5020, 17.21 -[6,7-3H]dimethyl-19-norpregna-4,9-diene-3,20-dione; R1881, of steroids in cytosol from 7,12-dimethylbenz(a)anthracene- 17j8-[6,7-3H]hydroxy-17a-methylestra-4,9,11 -trien-3-one (methyltrienolone); 170-{3H]estradiol, 17/H2,4,6,7,16,17-3H]estradiol; [3H]DHT, [1,2,4,5,6,7-3H]- dihydrotestosterone; [3H]DEX, [6,7-3H]-dexamethasone; HAP, hydroxylapatite; ' Supported by a grant from the National Cancer Institute of Canada. ¡.g.,intragastric; DES, diethylstilbestrol; DCC, dextran (0.05%)-coated charcoal 2 To whom requests for reprints should be addressed. (0.5%); R2858, 11/?-methoxyethinyl-17/3-estradiol; R2323, 13a-ethyl-17-hy- Received March 9, 1979; accepted January 25, 1980. droxy-18,19-dinor-1 7ß-pregna-4,9,11-triene-20yn-3-one. 1612 CANCER RESEARCH VOL. 40 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1980 American Association for Cancer Research. Binding of Steroid Markers in DMBA Tumors of steroid receptors has been performed using uniform tech were removed 11 days after the surgical treatment except for niques. For example, the exchange rate of all steroid classes the hypophysectomized animals, from which the tumors were has not yet been reported, such information being of major removed 7 days after surgery. Steroid binding was always importance for optimal binding measurement. Moreover, only determined using fresh cytosol. [3H]triamcinolone acetonide has been used for the assay of the glucocorticoid-binding component (13), while it is well known Homogenization and Cytosol Preparation that this tracer binds also to the progesterone receptor (6). All procedures, except where indicated, were performed at Another relevant aspect is that intact animals were generally 4°. Routinely, tissue was minced and homogenized with two used for the characterization of steroid-binding components in 10-sec bursts of a Polytron PT 10-ST (Brinkmann Instruments) DMBA-induced mammary tumors, thus leaving the possibility in 3 volumes of Buffer A (25 mM Tris-HCI-1.5 mw EDTA-10 mw of interference by endogenous steroids. Consequently, as a a-monothioglycerol-10% glycerol, pH 7.4). The homogenate first step, we have investigated in detail the binding character was centrifuged at 39,000 x g for 20 min, and the resulting istics of 4 classes of steroids (estrogens, androgens, proges- supernatant was centrifuged at 105,000 x g for 90 min in a tins, and glucocorticoids) in cytosol prepared from this exper Beckman L5-65 centrifuge, using a 50 Ti or 60 Ti rotor. Protein imental mammary tumor, using animals deprived of the endog concentration was determined according to Lowry ef al. (30), enous steroids studied. Moreover, in a second series of exper using bovine serum albumin as standard. Correction was made iments, we have studied the effect of adrenalectomy, combined for the slight interference by a-monothioglycerol. adrenalectomy and ovariectomy, or hypophysectomy on ste roid binding levels. Binding Assays After evaporation of the solvent under a stream of nitrogen, MATERIALS AND METHODS the labeled steroid was dissolved in Buffer B (10 mM Tris-HCI- Chemicals 1.5 mM EDTA-10 mM a-monothioglycerol, pH 7.4) and incu bated with the cytosol at the appropriate protein concentration. R5020 (51.4 Ci/mmol), R1881 (58.2 Ci/mmol), and the In order to measure nonspecific binding, a 200-fold excess of corresponding unlabeled steroids were synthesized at the the corresponding unlabeled steroid (except for 17/?-[3H]estra- Roussel Research Centre, Romainville, France, and were pro diol, where DES was used) was added to the corresponding vided by Dr. Jean-Pierre Raynaud. 17/H3H]Estradiol (152 Ci/ tubes, the incubation being performed in duplicate at 4°,gen mmol), [3H]DHT, (123 Ci/mmol), [3H]DEX (33 Ci/mmol), and erally using 100 ¿ilofthe tracer solution and 200 /¿Iofcytosol. [6,7,-3H]triamcinolone acetonide (33.7 Ci/mmol) were pur For [3H]R5020-binding assays, a 25-fold excess of unlabeled chased from New England Nuclear. The corresponding unla DEX was added to the incubation mixture to mask the gluco beled steroids, DMBA, and protamine sulfate (from salmon, corticoid-binding component. Grade 1) were products of Sigma Chemical Co. Charcoal (Norit A) was obtained from Fisher Scientific Co., while dextran T-70 Separation of Bound and Free Steroids was a product of Pharmacia Fine Chemicals, Inc. HAP (DNA- grade Bio-Gel HTP) was obtained from Bio-Rad Laboratories.
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