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

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The Effects of Glucocorticoids and Progesterone on Hormone Responsive Human Breast Cancer in Long-Term Tissue Culture1 [CANCER RESEARCH 36, 4602-4609, December 1976] The Effects of Glucocorticoids and Progesterone on Hormone responsive Human Breast Cancer in Long-Term Tissue Culture1 Marc Lippman, Gail Bolan, and Karen Huff Medicine Branch, National Cancer Institute, Bethesda, Maryland 20014 SUMMARY mon mechanism involving steroid-cyloplasmic receptor in heraction. This is followed by interaction of the steroid Glucocorticoids, at physiological concentration , inhibit receptor complex with the target cell ganome, leading ho call division and thymidina incorporation in three lines of accumulation of new species of mRNA that code for pro human breast cancer maintained in long-term tissue cul hems characteristic of the observed tissue-specific me tune. At steroid concentrations sufficient ho inhibit thymi sponses (4). dine incorporation 50%, little or no affect is seen on protein Glucocorticoids appear to be essential for the growth and synthesis 48 hr after hormone addition. All three of these differentiation of immature rat mammary gland in organ lines are shown to have glucocorticoid receptors demon culture (30). Similar effects have been noted in normal strable by competitive protein binding assays. Receptors human mammary gland in primary tissue culture (5). Gluco are extensively characterized in one line by sucrose density corticoids have also been reported to increase expression gradient analysis and binding specificity studies. Good con of mouse mammary tumon virus in tissue culture (20). De relation between receptor-binding specificity and biological spite these observations, suggesting a stimulahony role for activity is found except for progesterone, which binds to glucocorticoids in mammary cancer, pharmacological ad glucocorticoid receptor but is noninhibitony. Cross-compe ministration of glucocorticoids is eithen without effect or tihion and quantification studies demonstrate a separate leads to tumor regression in patients with breast cancer in receptor for progesterone. This receptor has limited bind about 15% of cases (27). The fact that adrenalectomy is ing specificitias restricted largely to progestahional agents, frequently a satisfactory form of palliation for metastatic whereas the glucocorticoid receptor bound both glucocom breast cancer may not be construed as evidence that gluco hicoids and progesterone. Two other human breast cancer corticoids inhibit the growth of mammary cancer. The lines neither contain glucocorticoid receptor nor are in mechanism of this effect has usually been ascribed hoabla hibiled by glucocorticoids. It is concluded that in some hion of C-19 precursors of andmogen and/or estrogen since cases glucocorticoids can directly limit growth in human physiological amounts of glucocorticoids must always be breast cancer in vitro without requiring alterations in other replaced following surgery (17). Thus, whether on not glu trophic hormones. cocorticoids have any direct effect on human breast cancer has remained moot since one might easily imagine that INTRODUCTION pharmacological doses of glucocorticoid could be palliative indirectly, as, for example, through suppression of the The estrogen-dependent nature of some breast cancer hypothalamic pituitary axis, in affect, a medical adrenal has bean amply demonstrated in clinical settings (3), animal ectomy. models (9), and recently in tissue culture (10). Physiological In this work, we describe the affects of glucocorticoids on concentrations of estrogen promote tumor growth, while 5 human breast cancer call lines maintained in tissue cul withdrawal of estrogen leads to either slower tumor growth tune for at leash 1 year. Some of these cell lines show on regression. Recent work has emphasized the importance marked inhibition of call division and precursor incorpo of an initial interaction between estrogen and specific cyto rated by glucocorticoids under conditions that preclude the plasmic receptor molecules as the 1st step in the pathway influence of other steroid on polypeptide hormones. Re through which steroid hormones regulate phanohypic sponsive calls contain high-affinity limited-capacity recap expression. tons for glucocorticoids demonstrable by competitive pro The role of glucocorticoids in human breast cancer is far hem binding analysis and sucrose density gradients. Bind lass clear. Glucocorticoids evoke strikingly diverse me ing is highly specific for biologically active glucocorticoids sponsas in different target tissues (28). Nonetheless, most and correlates reasonably with the dose response of these investigations have landed to support the notion that such cells ho steroids. disparate affects as enhanced RNA and protein synthesis in the liver (8) or lymphocyholysis (18) amamediated by a com MATERIALSAND METHODS , This is Paper 2 in a series on hormone-responsive human breast cancer cells in long-term tissue culture. Cells and Culture Techniques. Methodsfor establish Received November 4, 1975; accepted September 10, 1976. ment or sources of cell lines and their propagation are as 4602 CANCERRESEARCHVOL. 36 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1976 American Association for Cancer Research. Glucocorticoids and Breast Cancer in Vitro previously described (10). The human and mammary na pension, 0.8 ml, was added to 12- x 75-mm tubas. [3H]Dexa tunes of these cells have been substantiated by chromo methasone,0.2 ml, with or without an excess of unlabeled somal analysis, morphological features, and a-lactalbumin competitor was added to each tube and mixed. Tubes were synthesis (11).All lines havebeen maintained in culture for incubated at 0°for3 hr on37°for1 hr. Cells ware collected at least 1 year without loss of hormone responsiveness. by cantnifugation in a Senofuge (Clay-Adams, Parsippany, Precursor Incorporation and Growth. Methods for the N. J.), for 30 sec and washed twice in Dulbacco's phos measurementof [3Hjthymidineand ‘4C-labeledaminoacid phata-buffered saline; pH 7.4, supplemented with 5 mM incorporation including incubation times, labeling tech glucose. Cell buttons were suspended in water and son niques, and precursor specific activities havebeandetailed ically dispensed for 4 sec in a Branson sonicator at the previously (10, 11). Proteins wane determined using the lowest setting; aliquots were counted in Aquasol (NewEng technique of Lowry at a!. (14). All hormonal additions are land Nuclear, Boston, Mass.) in a Packard liquid scintilla done with cells maintained in 1% serum from which endog lion counter (efficiency for [3H], —35%). enous steroid and polypeptide hormones have been ma moved by treatment with activated charcoal (1). Removalof endogenous steroid is monitored by the addition of a small RESULTS amount of 3H-labeledsteroid to the serum and following removal of radioactivity by charcoal ho less than 1% (see The inhibitory effect of 10@ M dexamethasone on call also Ref. 11). As previously noted (10), these experiments growth of MCF-7human breast cancer is shown in Chart 1. can be performed with identical results using serum-free Dexamathasona inhibition is apparent after the 1st 24 hr in conditions. hormone as compared to cells in non-hormone-containing Steroid Receptor Assays. Sucrosedensity gradient anal medium. Despite diminished thymidine incorporation, glu ysis (7), dextran-coated charcoal assays,and multiple com cocorticoid-treahedcells multiply very slowly and, by phase petition studies (16)followed previously published methods microscopy, appearmorphologically indistinguishable from except as noted . Cytosols were incubated with Initiated control cells. steroid with or without an excess of unlabeled competitor The effect of dexamethasone on thymidine incorporation as described in the figure legend. Following a 2-hr incuba into DNA is shown in Chart 2. As indicated, thymidine incor lion at 0°,the cytosols were treated with dextran-coated poration is inhibited ho55% of control levels when inhibition charcoal (16) and layered onto sucrose gradients (7). Gra is measured after 48 hr of exposure to 5 x 10_6M dexameth dients were centrifuged at 275,000 x g for 18 hr at 4°in a asone. No concentration of dexamathasone is stip'iulahory. Beckman Model L5-65ultracentnifuge.[3H]Dexamethasona, Inhibition is apparent with as little as 5 x 10@M dexametha 22 Ci/mmole, and [3H]progestemone,86 Ci/mmole, were sona and is greater than 50% at 5 x 10_aM. The total obtained from Amensham/SeanleCorp.(Evanston, Ill.) and decrease in thymidina incorporation is lass than that in used without repunificahion.Unlabeled steroids were ob duced by anlieshnogens in the same cells for which pro tamed from Steraloids (Plattsburg, N. Y.). For competition longed incubation in 5 x 10@Mhamoxifan(ICI46474;trans studies, cytoplasmic extracts were added to 12- x 75-mm isomer of 1-[4-(2-dimatrylammnoethoxy)phenyI@-1,2-diphen chilled glass tubes containing unlabeled steroids as 1000- ylbuh-1-enacitrate) is lethal (10).Interestingly, there is insig fold concentrates. Immediately thereafter, [3H]dexamatha nificant inhibition by glucocorticoid of laucine inconpona sone (5 x 10@M)was added to each tuba. Following over lion into protein when protein synthesis is measured at 48 night incubation, specifically bound dexamethasone was assessedusing dextran-coated charcoal to separatebound 40 and free steroid. For competitive binding studies, competed and uncom peted tubes were generally nun in triplicate at each steroid concentration. Following overnight incubation at 4°,specif Control ically bound steroid was measuredby daxtran-coaled
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