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Receptor Characteristics of Specific Estrogen Binding in the Renal Adenocarcinoma of the Golden Hamster'

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Receptor Characteristics of Specific Estrogen Binding in the Renal Adenocarcinoma of the Golden Hamster' [CANCER RESEARCH 36, 1127-1132, March 1976] Receptor Characteristics of Specific Estrogen Binding in the Renal Adenocarcinoma of the Golden Hamster' Jonathan J. Li,2 Deanna J. Talley,3 Sara Antonia Li,2and Claude A. Villee Department of Biological Chemistry and The Laboratory of Human Reproduction and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02115 SUMMARY hormones on their respective target cells (4, 5, 15). Specific estrogen-binding protein receptors have been identified in Linear sucrose gradient analyses reveal that all estrogen such estrogen-sensitive tissues as the uterus, mammary induced and -dependent primary renal tumor cytosols ex gland, and hypothalamus (6, 17, 19), as well as in the di amined contain an 8 5 and variable amounts of 4 S receptor methylbenz(a)anthracene-induced mammary carcinoma in in low ionic buffer concentrations. Similar results were ob the rat and in human endometnial carcinoma (2, 20). King et tamed with extracts of primary metastases of these tumors. a!. (7) and Steggles and King (18) have reported the pres Sucrose gradients containing high salt (0.4 N KCl) convert ence of cytoplasmic 4 S or 8 S + 4 S and nuclear 5 S the 8 5 receptor in both the hamster renal tumor and uterus estrogen-binding complexes in the estrogen-induced renal to a 4 to 5 S complex. Scatchand plot analysis reveals that adenocancinoma of the golden hamster with some proper the renal tumor cytosol estradiol-necepton complex has a Ka ties similar to the uterine receptors. However, these studies of 1.7 x 10@M' and 9.2 x 10'° N binding sites. Competition indicated that the 8 S cytosol receptor was not a consistent for the tnitiated 17f3-estradiol binding sites in the renal tu finding in the transplanted primary renal tumor, whereas the mon was similar to that in the uterus with respect to estro serially transplanted, less estrogen-dependent tumor con genic compounds. Nonestrogenic steroids exhibited mini sistently contained both of these estrogen-binding moieties. mal competition at the same concentrations or higher. Sub This study was undertaken to describe more fully these stitution in the ring structure, particularly in position 3 of the receptors in the primary renal tumor and its metastases and phenolic A-ring, resulted in a considerable loss in the ability to compare the specificity of these receptors with those of such compounds to compete for these receptors. Anties found in the hamster uterus. Moreover, since antiestrogen trogens were effective competitors for these estrogen re treatment of tumor-beaning animals causes tumor regnes ceptors only at higher concentrations relative to the tnitiated sion (1), we have investigated the ability of such agents to estradiol. compete for these estrogen-binding sites. INTRODUCTION MATERIALSAND METHODS The renal adenocancinoma of the Syrian golden hamster Chemicals and Reagents. 17f3-[2,4,6,7-3H]Estradiol(105 (Cricetus auratus) represents an interesting system to study Ci/mmole) was obtained from New England Nuclear, Bos estrogen carcinogenesis, since only estrogenic hormones ton, Mass., and was found to be more than 98% pure by thin are necessary for its induction and maintenance (8). The layer chromatography on Eastman Kodak silica gel plates in carcinogenic action of estrogen in the initiation of these a solvent system described previously (12). Unlabeled 17f3- kidney tumors appears to be direct and peculiar to this estradiol, estrone, and estniol were provided by Calbiochem, species. San Diego, Calif., and all other unlabeled steroids were The selective uptake and retention of steroid hormones purchased from Sigma Chemical Co., St. Louis, Mo. Anties by steroid-dependent target tissues has been well docu trogens: CC4 was a gift from Dr. Alfred Richardson, Jr., mented, and their binding to cytoplasmic receptor proteins Menrell-National Laboratories, Cincinnati, Ohio, and U- has been implicated as an initial step in the action of these 11,100A was a gift of Dr. Harold M. Woodward and Dr. Gary 1SupportedbyGrantHD00006-12fromthe NationalInstituteof Child L. Neil, The Upjohn Company, Kalamazoo, Mich. Tnizma Health and Development; Grant CA 16854-01 from the National Cancer Insti base, Norit A, dextran 80, dithiothneitol, protamine sulfate, tute, NIH; and Research Service, Veterans Administration Hospital, Minneap catalase, bovine serum albumin, ovalbumin, potassium ohs, Minn. Presented in part at the 57th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlantic City, N. J., April 15 to chloride, sodium chloride, and TACE were obtained from 20, 1973. Sigma. Ultrapure sucrose (ANase-free) was purchased from 2 Present address: Department of Medicine, Veterans Administration Hos Schwarz/Mann, Onangeburg, N. V. pital, Minneapolis, Minn. 55417, and Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, Minn. 55455. To whom requests Animals and Tumor Induction. Young, mature castrated for reprints should be addressed, at Research Service, Building 49, Veterans Administration Hospital, 54th Street and 48th Avenue South, Minneapolis, 4 The abbreviations used are: CC(clomiphene citrate (cia)], 1-[p-(@-dieth Minn. 55417. ylaminoethoxy)phenyl]-1, 2-diphenyl-2-chloroethylene monocitrate; U- 3 Present address: Department of Nutrition, Massachusetts Institute of 11 bOA (nafoxidine hydrochloride), 1-{2-[p-(3,4 dlhydro-6-methoxy-2-phenyl Technology, Cambridge, Mass. 02139. 1-naphthyl)phenoxy]ethyl}pyrrolidine hydrochloride; TACE (chlorotriani Received September 19, 1975; accepted November 21, 1975. sene), tri-p-anisyl chloroethylene; DES, diethylstilbestrol. MARCH 1976 1127 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1976 American Association for Cancer Research. J. J. Li et a!. male and ovaniectomized female Syrian hamsters Sucrose Density Gradient Analyses. Tissue extracts (0.3 (LVG:LAK, outbned strain, Charles River; Lakeview Hamster to 0.4 ml) were layered on 4.6-mI linear 5 to 20% sucrose Colony, Newfield, N. J.), weighing 80 to 100 g and 100 to 110 gradients prepared in 10 m@ Tnis-HCI-1.5 mM EDTA-1 mM g, respectively, were used. Tap water and Ralston Purina dithiothneitol buffer, pH 7.4 using a gradient former (Buch laboratory chow were available ad libitum. Castrated males len Instruments, Inc., Fort Lee, N. J.). Sucrose gradients were acclimated at least 2 weeks prior to use, whereas the containing 0.4 M KCI were prepared similarly. The samples females were used 48 to 60 hr after ovaniectomy. DES or were centrifuged for 17 hr at 39,000 rpm in a Spinco L2 estnadiol-17f3 (Sigma) pellets (20-mg estrogen pellets were ultracentnifuge using either a SW 39 on SW 50.1 rotor at 4°. prepared by Dr. George M. Krause, Copley Pharmaceutical Gradient tubes were pierced with a 20-gauge needle and 9- Inc., Boston, Mass.) were implanted subpanniculanly as de drop fractions were collected in scintillation vials contain scnibed previously (10). Additional hormone pellets were ing 0.5 ml protosol (New England Nuclear) and assessed for implanted every 3 months in each animal to maintain estro radioactivity. gen levels. Renal tumors weighing 1 to 5 g/animal appeared Sedimentation coefficients were determined by the after 8 to 10 months of hormone treatment, and abdominal method of Martin and Ames (14), using catalase (11.3 5), metastases were common. A few male hamsters treated bovine serum albumin (4.6 5), and ovalbumin (3.7 5) as similarly had tumor weights greaten than 10 g/animal. The sedimentation markers. earliest tumor nodules were detected after 5 months of Uterine and tumor cytosols, when incubated with prota estrogen treatment. The pellets were removed 60 to 68 hr mine sulfate (7.5 mg/mI) for 10 mm, precipitated the necep prior to sacrifice to clear endogenous hormone. All animals ton according to the procedure described by Steggles and were exsanguinated under ether anesthesia and the tissues King (18). were immediately washed twice in cold 0.15 M NaCI in 10 Measurement of Radioactivity. The radioactivity in the mM tnis-HCI-1.5 mM EDTA-1mM dithiothneitol buffer, pH 7.4. sucrose gradient fractions was measured after adding 10 ml Preparation of Cytosol. The tumor tissue was freed of of a scintillation fluid mixture containing toluene-Liquifluon necrotic on hemorrhagic areas and tumor fragments were protosol (New England Nuclear) with a final protosol con weighed and then homogenized in 2.5 on 3.0 volumes of centration of 10%. All non-gradient samples were counted cold 10 mM Tnis-HCI, 1.5 mM EDTA, 1 mM dithiothreitol in a similar mixture containing 5% protosol. Samples were buffer, pH 7.4, using a chilled Teflon Potter-Elvehjem-type counted at 5°ina Packard Tni-Carb liquid spectrometer with homogenizer. Cytosols from uteri were prepared similarly, a counting efficiency of approximately 38% for tnitium. except that homogenization was carried out in a conical ground-glass homogenizer. Tissue homogenates were cen tnifuged in a Spinco L2 ultracentnifuge for 60 mm at 5°and RESULTS 100,000 x g. After centnifugation, the supennatant fluids (cytosols) were then filtered through a Millex filter, 0.45 Relative Binding of Tritiated Estradiol in the Untreated pm), (Millipone Corp., Bedford, Mass.) to remove residual Kidney, Estrogen-treated Kidney, and Renal Tumor Cyto lipid and cell debris. sols. A comparison of estrogen binding in renal cytosol Protein concentration of the cytosols was determined by fractions from untreated castrate, estrogen-treated castrate, the method of Lowry et al. (13), using bovine serum albumin and tumor-bearing hamsters was made. We have reported as a standard. previously that a specific 4 S estrogen-binding protein is In Vitro Incubation of Specific Estrogen Binding. Aliquots present in the renal cytosols of castrated and estrogen (0.5 on 1.0 ml) of the cytosol fraction were incubated in vitro treated hamsters (12). It is estimated, based on total radio with 1 x 10-@@M17f3-[3Hjestradiol prepared in 30% ethanol in active estradiol binding after dextran-chancoal minus com 0.15 N NaCI solution.
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