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The Effects of Androgens and Antiandrogens on Hormone Responsive Human Breast Cancer in Long-Term Tissue Culture1

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The Effects of Androgens and Antiandrogens on Hormone Responsive Human Breast Cancer in Long-Term Tissue Culture1 [CANCER RESEARCH 36, 4610-4618, December 1976] The Effects of Androgens and Antiandrogens on Hormone responsive Human Breast Cancer in Long-Term Tissue Culture1 Marc Lippman, Gail Bolan, and Karen Huff MedicineBranch,NationalCancerInstitute,Bethesda,Maryland20014 SUMMARY Information characterizing the interaction between an drogens and breast cancer would be desirable for several We have examined five human breast cancer call lines in reasons. First, androgens can affect the growth of breast conhinuous tissue culture for andmogan responsiveness. cancer in animals. Pharmacological administration of an One of these cell lines shows a 2- ho 4-fold stimulation of drogens to rats bearing dimathylbenzanthracene-induced thymidina incorporation into DNA, apparent as early as 10 mammary carcinomas is associated wihh objective humor hr following androgen addition to cells incubated in serum regression (h9, 22). Shionogi h15 cells, from a mouse mam free medium. This stimulation is accompanied by an ac many cancer in conhinuous hissue culture, have bean shown celemation in cell replication. Antiandrogens [cyproterona to be shimulatedby physiological concentrations of andro acetate (6-chloro-17a-acelata-1,2a-methylena-4,6-pregna gen (21), thus suggesting that some breast cancer might be diene-3,20-dione) and R2956 (17f3-hydroxy-2,2,1 7a-tnima androgen responsive in addition to being estrogen respon thoxyastra-4,9,1 1-Inane-i -one)] inhibit both protein and siva. DNA synthesis below control levels and block androgen Evidence also indicates that tumor growth in humans may mediahed stimulation. Prolonged incubahion (greahenhhan be significantly altered by androgens. About 20% of pahianhs 72 hn) in antiandrogen is lethal. The MCF-7 cell line conhains with metastahic breast cancer will show objective tumor high-affinity receptors for androganic steroids damonstra regressions when treated wihh androgens (1). A somewhat bla by sucrose dansihy gradients and competitive protein higher proportion of patients will respond to adnenalechomy binding analysis. By cross-competition studies, androgan (4). The efficacy of hhis latter therapy has bean attributed to receptors are distinguishable from estrogen receptors also the removal of androgen precursors of adrenal origin, pni found in this cell line. Concentrations of steroid that sahu manly dehydnoepiandrostamone and t@4-androstenedione. mateandrogen receptor sites in vitro are about 1000times Clean-cut evidence that human breast cancer is androgen lower hhan concentrations hhat maximally shimulate the dependent has not, however, been previously available. cells. Changes in quantity and affinity of androgen binding Finally, andmogen receptor proteins have recently been to intact cells at 37°ascompared with usual binding tech demonstrated in some human breast cancer samples (3, 9, niques using cyhosol preparation at 0°do not explain this 12) and have been shown to be distinct from both estrogen difference between dissociation of binding and affect. How receptor and sex steroid-binding globulin. It is clear that ever, this difference can be explained by conversion of [3H]- most if not all steroid hormone actions are mediated by an 5a-dihydmohastosherona to 5a-andnoshanediol and mona po initial interaction of steroid hormone and receptor (h3). Ianmatabolihas at 37°.Anexamination of incubation media, Since estrogen receptor determination in human breast cytoplasmic extracts, and crude nuclear pellets reveals cancer appears to be of value in guiding therapeutic deci probable conversion of [3H]lashoslerone to [3H]-5a-dihydro sions in the management of metashaticbreast cancer by testosterone. Our data provide compelling evidence that predicting which patients will respond ho hormonal man ipu some human breast cancer, at least in vitro, may be andro lahions (14), it is reasonable to hope that further delineation gen dependent. of hhe mechanism of inheraction of androgens wihh breast cancer might also havetherapeutic implications. Study of these processes, however, has been hampered iNTRODUCTION by the lack of a suitable modal system in which the action of one hormone could be studied independently of the actions We have recently examined several call lines of human of ohhemImophic hormones. In addition, in vivo model sys breast cancer maintained in long-term tissue culture. The tems for androgen action are significantly perturbed by hormone responsiveness of some of these cell lines to interactions of androgen with sex steroid-binding globulin estrogen (6, 7) and glucocorticoid (8) encouraged us to as well as by effects of androgens on concentrations of examine the effects of androgens and antiandrogens. many ohhenhormones including gonadotrophins, prolachin, and estrogen (18). I This is Paper 3 in a series on hormone-responsive human breast cancer cell lines in long-term tissue culture. We now report the characterization of an androgen-re Received November 4, 1976; accepted September 10, 1976. sponsive human breast cancer call line grown in continuous 4610 CANCER RESEARCH VOL. 36 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1976 American Association for Cancer Research. Androgans, Breast Cancer, and Tissue Cu!tura tissue culture that obviates the above difficulties. And rogan Variation in cell counts for any group of dishes was about effects are demonstrable in totally defined medium that 10%. contains no additional hormonal or serum factors. We are Thymidine and Leucine Incorporation Studies. Calls optimistic that such a model system may significantly aid in growing in log phase were harvested in hmypsin-EDTAand hha study of mechanisms of androgen responsiveness. plated in 6-place Linbno dishes (BalIco Glass, Inc. , Vine land, N. J.) in MEM supplemented with 5% fetal calf serum. The next day the medium was changed to MEM without serum. The following day the serum-free medium was again MATERIALSAND METHODS replenished, and hormones ware added as noted in the various chart legends. Two hr before harvesting, radioac hive nucleoside and/on amino acid were added to each well, Cells and CuftureTechniques.Methodsfor propagation and the cells wane harvested as previously described (6, 8). of cells are as previously described (6, 7).2All cell lines have Whole-Cell Binding Experiments. Calls growing in MEM been maintained for ah least 1 year without changes in plus 5% fatal calf serum were changed to MEM without responsiveness. All lines have been tested for Mycop!asma serum on the day prior to the start of the experiment. Calls (Flow Laboratories, Rockville, Md.) and wane shown to be were harvested by suspension in tmypsin-EDTA and were free of contamination. All cell lines used in the present washed twice in PBS. The cells ware than dispersed in MEM shudy synthesize enzymahically active a-lactalbumin. (M. E. supplemented with 25 m@i N-tmis(hydmoxymethyl)methyl Lippman and B. Vondarhaan, unpublished observations; a- glycina (pH 7.2) at a densihy of about h06/ml. Calls ware lactalbumin activity was detected using an enzymahic assay then added to 12- x 75-mm glass tubes containing [3H]- in which call homogenates are incubated with [‘4C]UDP 5a-DHT at various concentrations with on without a 1000- galactose and formation of [“C]lactosaismeasured.) fold excess of unlabeled 5a-DHT. Tubas were shaken in a SucroseDensityGradientAnalysisandBindingStudies. waler bath at either 0°for 3 hr or 37°for 1 hr. At the and Analysis of androgan receptors on sucrose gradients and by of the incubation, the medium was diluted with 3 ml of iced competitive protein binding assay was as previously de PBS, and the cells ware collected by cantnifugation for 30 scnibed (6, 8). Briefly, 100,000 x g supemnatants of cell sac in a Clay Adams sarofuge. The calls were washed twice homogenates were prepared and incubated with 5 x 10@ M in ice-cold PBS, suspended in 0.5 ml of distilled water, and [3H]-5a-DHT3 with or without competitor. After treatment sonically dispersed for 4 sac at the lowest salting in a Bran wihh dextran-coated charcoal, these extracts were layered son sonicaton; aliquohs wane taken for protein datenmina onto 5 to 20% sucrose gradients in 10% glycerol. The purity lion by the technique of Lowry at a!. (11) or counted in of [3H]DHT(107Ci/mmole; AmershamSearleCorp., Evans Aquasol (New England Nuclear, Boston, Mass.) in a Pack ton , Ill.) was checked by thin-layer chromatography (10) and and liquid scintillation counter (efficiency for Inilium, was shown to be more than 98% radiochemically pure. For —40%).Results ware analyzed by the method of Scatchand studies designed to examine the specificity of binding, au (20). quots of cyhoplasmic extract ware pipetted into tubas con Conversion of 5a-DHT to 5a-Androstane-3a,17/JdiOl. T taming various concentrations of unlabeled steroid as 1000- 75 flasks of confluent MCF-7 cells ware incubated at 37°in fold concentrates in ethanol. Radiolabeled steroid, eihhen 10 ml of serum-free MEM containing 10@ M [3H]-5a-DHT (44 1 0@ M [3H]-5a-DHT as above on 1 7f3-[3H]estradiol (1 00 Ci/ Ci/mmole) for 0, 1, 4, and 8 hr. The medium at each lime mmola; Amarsham Seanla), was added immediahaly thareaf point was collected and extracted with 2 volumes of methyl her. Labeled steroid was used at 10@ M, which is only ene chloride. The organic phase was separated by centnifu slightly above the dissociation constant for the receptor and gation and evaporated to dryness under nitrogen. The resi therefore not saturating, in order to keep nonspecific bind dues were redissolvad in 1 ml of methylene chloride con ing below 10% of the total binding. taming 200 @geach of androshanediol, andnostenadione, Effect of Androgens on Cell Growth. Cells growing loga testosterone, and 5a-DHT. Fifty @lwereapplied to duplicate nithmically were harvested with sterile 0.02% EDTA and thin-layer Silica Gel G plates (20 x 20 cm) (Analtech, Inc., plated in 60-mm sterile plastic PaIn dishes in MEM with Newark, Del.), and the chromatognams were developed by serum. After 24 hr, the medium was changed to medium ascending chromahography in chloroform :methanol (98:2, wihhouh serum.
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