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Dehydroepiandrosterone Sulfotransferase As a Possible Shunt for the Control of Steroid Metabolism in Human Mammary Carcinoma1

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Dehydroepiandrosterone Sulfotransferase As a Possible Shunt for the Control of Steroid Metabolism in Human Mammary Carcinoma1 [CANCER RESEARCH 37, 278-284, January 1977] Dehydroepiandrosterone Sulfotransferase as a Possible Shunt for the Control of Steroid Metabolism in Human Mammary Carcinoma1 J_ B. Adams2 and D. P. Chandra2 ImperialCancerResearchFund,Lincoln's Inn Fields,London,England(J. B. A.), and the Schoolof Biochemistry,Universityof NewSouth Wales, Kensington,AustraliafJ. B. A., D. P. C.) SUMMARY noid moiety can occur with the sulfate group intact, but such pathways appear to be of minor significance (21). Human primary mammary tumors were examined to de Oao and Libby (15, 16) have demonstrated that the sulfur termine what factors were of importance in deciding relative ylation of steroids by human mammary carcinoma tissue is rates of sulfurylation of dehydroepiandrostenone and 17$- highly correlated with prognosis and response to hormone estradiol, such rates having been shown to correlate with ablative procedures such as adnenalectomy. In patients un the patient's prognosis and response to adrenalectomy (T. dengoing adnenalectomy for late-stage breast cancer, the L. Oao and P. A. Libby. Enzymic Synthesis of Steroid Sul failure of tumor preparations to sulfurylate steroid hon fate by Mammary Cancer and Its Clinical Implications. NatI. mones in vitro was related to a particularly grave prognosis Cancer Inst. Monographs, 34: 205-210, 1971). The sulfur and a complete lack of response to adrenalectomy. When ylation of dehydroepiandrosterone and 17f3-estradiol was DHEA3 and 17f3-estradiol were compared as substrates for studied in 41 tumors in vitro using tumor cytosol, adenosine tumor sulfotransferases, then if the ratio of DHEA sulfate tniphosphate, [35S]SO42, Mg2@,and added steroid. Six tu formation to 17f3-estnadiol sulfate formation was <1, this mors showed no sulfurylating ability, 9 sulfurylated dehy was also associated with a poor prognosis and response to droepiandrosterone at a rate greater than that for 17$- adrenalectomy. The group with the best response and prog estradiol (ratio, >1), and 26 sulfunylated dehydroepiandnos nosis showed DHEA sulfate:17f3-estnadiol sulfate ratios of tenone at a rate lower than that for 17f3-estradiol (ratio, <1). >1 . In studies on primary tumors examined at the time of Evidence was obtained that low levels of dehydnoepiandros mastectomy, these ratios were also correlated with prog terone sulfotransfenase were responsible for ratios of <1 , in nosis, as witnessed by the presence of metastases or by many instances. Adenosine 3'-phosphate 5'-phosphosul early recurrence (16). fate synthesis and steroid sulfotransfenase activities were Lowered ratios of DHEA sulfate to 17f3-estnadiol sulfate measured in 30 tumors. A significant correlation was found could be due to either decreased DHEA sulfurylation or between synthesis of the former and levels of estrogen increased 17f3-estradiol sulfurylation. In this investigation, sulfotransferase, but this relationship did not hold for dehy human mammary tumors were examined for their overall droepiandrosterone sulfotnansferase, again due to low 1ev ability to form steroid sulfates from S042_and, in an associ els of this enzyme in many tumors. It is suggested that ated study, for their ability to form the intermediate PAPS dehydnoepiandrosterone sulfate formation in the tumors is and catalyze subsequent transfer of the sulfate group from mainly controlled by the sulfotnansfenase, which acts as a PAPS to added steroids. In this manner, the limiting steps in shunt in regulating the level of free dehydroepiandroste steroid sulfunylation were assessed. none, and related compounds, available for metabolism to steroids influencing the growth of mammary epithelial cells. MATERIALS AND METHODS INTRODUCTION TumorTissue Human mammary carcinoma tissue can sulfurylate ste Specimens of primary carcinoma tissue from patients roids (3) and convert steroids into physiologically active undergoing mastectomy were received from the operating metabolites (7). Of particular significance is the ability of theater. They were placed in plastic containers packed in some breast tumors to produce estrogens (1, 5, 7, 23). The ice, transported to the laboratory, and stored at —20°.The significance of the sulfunylation process in steroid hormone time between receiving the specimen and freezing it did not -@ metabolism remains unclanified . Transformations of the ste exceed 1 hr in any instance. Subsequently, the tissue was allowed to thaw, fat and connective tissue were removed, I Supported by grants from the New South Wales Cancer Council and the Australian National Health and Medical Research Council. 2 Permanent address: School of Biochemistry, University of New South 3 The abbreviations used are: DHEA, dehydroepiandrosterone; PAPS, Wales, P. 0. Box 1, Kensington, N. S. W. 2033, Australia. adenosine 3'-phosphate 5'-phosphosulfate; APS, adenosine 5'-phosphosul Received May 26, 1976; accepted September 1, 1976. fate. 278 CANCER RESEARCH VOL. 37 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1977 American Association for Cancer Research. Steroid Sulfotransferases and Breast Cancer and a weighed sample (0.2 to 1.0 g) was cut into small room. After drying, the strips were scanned in a Nuclear pieces and frozen in the barrel of a stainless steel chamber Chicago Actigraph Ill instrument. The [35S]PAPS and prechilled in dry ice. The frozen tissue was shattered by [35SJAPSpeaks were identified by comparison with authen hammering a closely fitting stainless steel plunger into the ticcompounds. Areasofthesepeakswere measured,and chamber. (Details of this piece of equipment can be ob the activity of the PAPS-synthesizing system was expressed tamed from the authors.) The resulting fine powder was in arbitrary units defined as the sum of the areas of PAPS transferred to a small glass homogenizer, 4 volumes of 0.01 plus APS per mg of cytosol protein used in the incubation. Msodiumphosphatebuffer(pH7.4)in0.9%NaCIsolution Assay of Acid MucopolysaccharideSulfotransferase. were added, and the mixture was homogenized using a The incubation mixture was identical to that for the control Teflon plunger. The cytosol fraction was collected after in Paragraph 1. After 2 hr of incubation at 37°,10ml of 0.2 M centnifugation at 100,000 x g for 1 hr. Na2SO4and 1 ml of 1% (w/v) aqueous solution of sodium In all cases histological diagnosis of carcinoma was con chondroitin sulfate (Sigma) were added. After mixing, 1 ml firmed from block sections. of 5% (w/v) aqueous solution of cetyl tnimethylammonium bromide (Hopkin and Williams Ltd., Essex, England) was Chemicals added, and the precipitate was allowed to stand for 1 hr on overnight if floculation was delayed. The precipitate was DHEA, DHEA sulfate, 17f3-estradiol, and APS were ob centrifuged down and washed with 5 ml of 0.1 M Na2SO4. tamed from Sigma Chemical Co., St. Louis, Mo. Cholesterol This was repeated 4 times, followed by 1 washing with was obtained from the British Drug Houses Ltd., London, water. Finally, the precipitate was centrifuged, the superna England. Estrone 3-sulfate was purchased from Ikapharm, tant was discarded, and the tube was drained by inversion Ramat-Gan, Israel. 17f3-Estradiol 3-sulfate was prepared on tissue paper. The precipitate was dissolved in 2 ml of from this by NaBH4 treatment. Cholesteryl 3-sulfate was 10% (w/v) NaCI and sodium salts of acid mucopolysaccha prepared by the method of Joseph et al. (21). [35S]Sulfate, rides precipitated by addition of 1.5 volumes of ethanol. carrier-free, was purchased from the Radiochemical After standing for 2 hr at 0°,the material was centrifuged Centre, Amensham, England. and the process of dissolution and precipitation was re peated. The material was dissolved in 1 ml of water, and 0.2 Protein ml was removed for counting in 10 ml of detergent-phos phor (see Paragraph 1). Blanks carried out with bovine This was measured by the method of Lowry et a!. (22). serum albumin in place of tumor cytosol were zero. The identification of the radioactive fraction isolated by this Conditionsof Incubationand AssayProcedures procedure as acid mucopolysacchanide was demonstrated as described previously (2). 1. Assay of Steroid Sulfotransferases.The incubation mixture contained the following ingredients in a total vol Examinationof Ester [35SJSuIfatesFormedfrom Endoge ume of 0.2 ml: 1 @tmoIeATP;1.5 @molesMgCI2;0.01 mmole nousAcceptors Tnis-HCI, pH 7.4; 0.04 @moleNa2SO4;25 pCi carrier-free [35S]SO42; 0.1 ml cytosol fraction of tumor; and 0.01 @moIe Incubations of cytosol fractions of a number of tumors, in steroid added in 0.01 ml propylene glycol. Controls con the absence of added steroid, were carried out as in Para tamed o.oi ml propylene glycol. Incubation was for 2 hr graph 1, but on 3 times the scale and in the presence of a at 37°.The steroid [35S]sulfate formed was assayed by total of 80 pCi of [35Sjsulfate. Reaction was stopped by extraction into ethyl acetate (14). Briefly, 2 ml of 2 NNA4OH, addition of 1.5 volumes of ethanol and protein was removed saturated with (NH4)2SO4,were added, and the mixture was by centnifugation. The supennatant was then chromato extracted with ethyl acetate (3 x 3 ml). The combined ex graphed on paper. tracts were adjusted to 10 ml and back-extracted once with 0.5 ml of seven-eighths-saturated (NH4)2S04.An aliquot (3 PaperChromatographySystems ml) was evaporated in a vial, 10 ml of detergent-phosphor were added (3), and samples were counted by liquid scintil System A: ethanol:1 M ammonium acetate, pH 7.5 (7.5:3). lation. Sufficient counts were recorded to allow for an accu System B: 0.4 M sodium phosphate, pH 6.3. System C: racy of 3%. After counts were subtracted in the control (all diisopnopyl ethen:tert-butyl alcohol:concentnated ammo ingredients but no steroid), the net counts were expressed nia:waten (6:4:1:9). Steroid sulfates on chromatograms as pmoles of steroid sulfate per mg protein per 2 hn, from a were cleaved to the free steroids by exposure to HCI vapor knowledge of the specific activity of the [35S]sulfate.
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