Inhibition of Prolactin-Induced Mammary Cancer in C3hf (XVII) Mice with the Frans Isomer of Bromotriphenylethylene1

[CANCER RESEARCH 40, 1674-1679, May 1980] 0008-5472/80/0040-OOOOS02.00 Inhibition of Prolactin-induced Mammary Cancer in C3Hf (XVII) Mice with the frans Isomer of Bromotriphenylethylene1

Michel Drosdowsky, Marc Edery,2 MichÃ¨le Guggiari, America Montes-Rendon, Georges Rudali, and Claude Vives

Laboratoire de Biochimie, Centre Hospitalier et Universitaire de Caen. CÃ´te de Nacre. 14040 Caen Â¡M.D.. M. E.Â¡.and Equipe de Recherches 190 du Centre National de la Recherche Scientifique. Fondation Curie, 26. rue d Ulm. 75005 Paris. France Â¡M.G.. A. M-R.. G. R., C. V.Â¡

ABSTRACT under the kidney capsule, 90% presented such cancers (33). It was shown recently in life span experiments that a brominated C3Hf (XVII) mice never develop spontaneous mammary tu triphenylethylene, commonly known as broparestrol, adminis mors. However, the transplantation of an isologous pituitary tered to pituitary-transplanted young C3Hf (XVII) females, in gland under their kidney capsule is followed by a 10-fold hibits the development of mammary glands (22) and of mam increase in serum and pituitary prolactin content (180 ng/ml mary carcinogenesis (33). Broparestrol presents 2 isomer and 20 /ng/mg of tissue, respectively), concomitant with an forms like clomiphene, another derivative of triphenylethylene, increase of prolactin receptors in mammary glands. Under of which both isomers have been reported to produce different these conditions, mammary tumors appear in 90% of the mice. reactions in experimental animals (15, 16). Accordingly, we If a racemic brominated triphenylethylene, i.e., broparestrol, decided that it would be interesting to study separately the is administered, serum and pituitary prolactin decrease rapidly biological activities of the frans and the c/s forms (Chart 1). (10 ng/ml and 4 mg/mg of tissue, respectively), and prolactin In the present work, we will report some of our results receptors in the mammary gland are markedly reduced. This obtained with the frans isomer, TBP.3 compound also inhibits the development of normal mammary glands, prevents mammary carcinogenesis, and unexpectedly MATERIALS AND METHODS causes a significant atrophy of the ovaries. Our study confirms that prolactin is a key hormone involved Two hundred sixty C3Hf (XVII) females (colony of the Curie in murine mammary carcinogenesis and that it can act directly Fondation), 25 to 30 days old, were used for the biological on the mammary gland by stimulating the level of its own experiments. An isologous male pituitary gland transplantation receptor. under the left kidney capsule was performed on all of them. Fourteen mice received no other treatment. Seven mice were INTRODUCTION sacrificed on the 25th day. Fourteen mice received a diet containing 2 ppm (7.5 fig TBP per mouse per day), 14 received Prolactin plays a major role in the etiology of mammary a 20-ppm diet, and 14 others received a diet containing 200 tumors in rodents (3, 24, 31, 47). It is now established that a ppm of the compound (22). Seven more were sacrificed on the high blood level of prolactin produces, with great frequency, 25th day, and the remaining 7 mice were sacrificed on the 50th adenocarcinomas in mice of every strain, even if the animals day. A complete autopsy was performed on all the animals. do not harbor the mammary tumor agent (24). Such a high Furthermore, the 4th left mammary gland from each mouse level can be induced by grafting an isologous pituitary under was prepared for a whole-mount dissection (22). the kidney capsule, as was first demonstrated by Desclin (9). The 204 remaining mice were divided into 4 groups and It was further demonstrated (49) that drug-induced suppression received the same diets that the 56 others received, i.e., normal of prolactin secretion in pituitary isograft-bearing mice resulted diet or diets containing 2, 20, or 200 ppm of the drug, and in a sharp reduction in the incidence of mammary tumors. It were observed in a life span experiment. appeared also that there was a clear correlation between the Most of the mice were sacrificed when moribund. Sponta concentration of serum prolactin and spontaneous mammary neous death was exceptional. An autopsy was performed on carcinogenesis in control females. High-mammary-cancer C3H each of them. Mammary tumors, grafted and in situ pituitary mice have an elevated level of prolactin, whereas low-mam glands, adrenal glands, ovaries, uterine horns, and occasional mary-cancer C57BL mice have a decreased level at 250 days pathological findings such as liver lesions or pulmonary tumors (40). were fixed in Bouin-Hollande fluid for a routine microscopic The demonstration that prolactin is one of the major factors examination after hematoxylin-eosin-safran staining. in the etiology of mammary cancer in rodents initiated a great The biochemical experiments were carried out on 175 fe amount of research on antiprolactinic compounds of various males at 30 days of age. The mice were divided into 16 groups chemical structures (8, 17, 23, 25, 26, 29, 30, 41, 43, 46). as shown in Table 1. They were killed by cervical dislocation; The C3Hf (XVII) females which were used in our experiments blood was collected by cardiac puncture and allowed to clot at never developed any spontaneous mammary tumors. However, 4Â°.Serum was separated and stored at â€”¿20Â°untiluse. One following the transplantation of an isologous pituitary gland mammary gland and the pituitary from each mouse were im mediately excised, weighed, and stored at -20Â°. ' Supported by grants from Ligue DÃ©partementale de Lutte contre le Cancer. Highly purified bovine prolactin (NIH-P.B. 4) was used for Presented in part at the First International Congress on Hormones and Cancer. Rome, Italy, October 1979. binding studies. Dr. N. Y. Sinha supplied us with the reagents * To whom requests for reprints should be addressed. Received September 28. 1979; accepted January 23. 1980. 3 The abbreviation used is: TBP, (rans-broparestrol.

1674 CANCER RESEARCH VOL. 40

prolactin (10 /ig/ml solution), or 100 fi\ of buffer and 100 jul of 125l-labeled prolactin (150,000 dpm = 1 ng, approximately). The tubes were incubated for 2 hr at 25Â°or for 24 hr at 4Â°, according to the methods of Sakai ef al. (34) and Powell ef al. (28). Scatchard analyses (35) were carried out with increasing concentrations of 125l-labeled prolactin in the presence or ab sence of a 2,000-fold excess of unlabeled bovine prolactin (the molecular weight of prolactin was assumed to be 23,000). Cold buffer (3 ml) was added to each tube, and the membranes were Br precipitated by centrifugation at 2,000 x g for 20 min at 4Â° and then counted in a Packard Tri-Carb scintillator with a 30% efficiency. All tissues from 4 to 10 animals were pooled, and

CIS-BROPARESTROL TRANS-BROPARESTROL results included in the paper are based on duplicate determi nations. Chart 1. Structure of cis- and (rans-broparestrol (bromotriphenylethylene).

Table 1 RESULTS Groups of mice used for biochemical experiments No. of TBP (20 ppm) Days after TBP As shown in Figs. 2 to 4, the development of the mammary mice in diet treatment glands is strongly inhibited by the 2 high doses, and to a lower ControlmicePituitary degree by the dose which corresponds to a daily intake of 6 to +77 8 /ig/mouse. The inhibition appears even after a short time,

+77 i.e., 25 days, and seems more pronounced after 50 days. In fact, these results are similar to those obtained with the trans- isograft-bearing mice77 cis mixture (22). Administration of TBP in life span experiments +3535 produced particularly interesting results. As could be expected, +714 the 2 high doses suppressed completely mammary carcinogenesis, as was the case with broparestrol (33). However, it +77 should be remembered that this last compound, incorporated +77 in the diet at a level of 2 ppm, did not prevent the tumor appearance. At the same dose, the frans isomer produced a +77 nearly total inhibition. Only one tumor was observed in a group +151513013015152020353550508585125125of 54 mice (Table 2). It appears in Table 3 that the pituitary isograft produced a hypertrophy of the ovaries, probably due for radioimmunoassay of mouse prolactin. For Â¡ordinationof to the development of several corpora lutea. In mice treated prolactin, carrier-free Na125lwas obtained from the Radiochem- ical Centre, Amersham, England; lactoperoxidase was ob Table 2 Mammary carcinogenesis of female C3Hf mice bearing a transplanted pituitary tained from Calbiochem, Los Angeles, Calif., and diluted per and receiving TBP oxide was from Mallinckrodt Chemical Works, St. Louis, Mo. tumorsTreatmentTBP Mice with Hormone Assay. The prolactin content of the pituitary glands and sera was measured by specific homologous radioimmu ofmice35405475No.00153%001.570.6Meanwithouttumorslatency vivai (days)709722556(days) tumors noassay. The assay procedure is that of Sinha ef al. (38) with some modifications. Mouse prolactin was iodinated using the (200ppm)TBP (20ppm)TBP lactoperoxidase method as described by Frantz and Turkington (2ppm)None 707306 (13) and yielded 125l-labeled prolactin with a specific activity of (controls)No. 4 16 83 mCi/mg. The separation of bound and free prolactin was performed by double-antibody immunoprecipitation, using Table 3 sheep anti-rabbit y-globulin immunosorbent linked to a cellu Weight of different glands of female C3HI (XVII) mice bearing a transplanted lose derivative (double-antibody solid phase from Organon, pituitary and receiving TBP (mg)25th Ovaries (mg)4.2 (mg)2.6 Teknika S.A., Paris, France). dayControls Preparation of Tissue Particles. The fourth abdominal mam (6)2 5.4 Â±1.2a Â±0.83.9 Â±0.41.28 mary glands were quickly excised and chilled. For the prepa (7)c20ppm 4.1 Â±1 Â±0.5Â°4.8 Â±0.17a1.58 Â±0.9(7)c4.5 Â±0.22d1.46 ration of a crude low-speed pellet, the method of Turkington weighed200ppm Not (4)"50th ppm 2.3 Â±0.4 Â±1C4.3 Â±0.3rf2.60 (44) was used. Highly purified cell membrane fractions were prepared by sequential centrifugation at 15,000 and 100,000 dayControls 1.2(7)2 9.7 Â± Â±0.83.6 Â±0.51.16 x g (37). The 100,000 x g pellet was resuspended in 2.5 mw (7)"20ppm 4.3 Â±0.7 Â±0.22C3.7 Â±0.28a1.11 Tris-HCI buffer (pH 7.4) containing 10 HIM CaCI2 and 0.1% (6)d200ppm 2.0 Â±0.3 Â±0.3C4.6 7d1.56Â±0.1 bovine serum albumin, and the protein concentration was es (6)0"03e" ppm 2.8 Â±0.4 Â±0.8Â°Pituitaries Â± timated according to the method of Lowry ef al. (20). The Mean Â±S.E.Adrenals specific binding of 125l-labeled prolactin was determined as mice.cNumbers in parentheses, number of control.dNonsignificant versus follows. To 100 /il of the membrane preparation containing 100 controls.ep < 0.01 versus to 300 /ig of protein were added 100 jul of unlabeled bovine p < 0.05 versus controls.

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1980 American Association for Cancer Research. M. Drosdowsky et al. with TBP, the weights of the ovaries remained similar to those usually observed in 2- to 3-month-old mice. It is well known that ovaries of such young females do not secrete progester one. The biochemical investigations on the receptors in mammary 2010I glands revealed that their level was in all cases too low to be detected in crude particulate extracts. Therefore, we used only membrane fractions to determine the binding capacity. Scat- o chard analyses gave an apparent Kd of approximately 10~9 M. z o Chart 2 shows that the level of circulating prolactin increases z gradually in grafted mice as compared to the nongrafted ani m mals. In all cases, treatment with TBP results in a significant reduction of serum prolactin. Chart 3 shows the same patterns for pituitary secretion of prolactin as those obtained for serum prolactin, indicating that ^~\bControl the graft induces a continuous secretion of the hormone and Control Grafted Grafted + animals animals that TBP administration suppresses it. i iÂ¡I1 +TBP Chart 4 shows that after 20 days the specific binding of Chart 4. Effect of 20 days of TBP treatment on specific binding of 125l-labeled prolactin in mammary glands is more important in grafted mice prolactin to mice mammary gland membranes as measured at 4Â°. a versus than in all the other groups. TBP treatment induces a significant control, not significant; b versus control, p < 0.01 ; c versus b, p< 0.01. decrease in binding both in control and in grafted mice. As shown by Chart 5, the binding capacity at 25Â° is more important as a result of the exchange procedure that occurred 50

Â£ 1â€” S 150 o z z 25ControlaControl >- u D < 2 _j D o K U O. 2 3 ce o.

Grafted animac1 s animals TBPbGraftei + T B P Chart 5. Effect of 20 days of TBP treatment on specific binding of '25l-labeled 40 65 90 115 DAYS TREATMENT prolactin to mice mammary gland membranes as measured at 25Â°. a versus control, p < 0.05; b versus control, p < 0.05; c versus b, p < 0.01. Chart 2. Effect of TBP treatment on serum prolactin concentration. â€¢¿grafted animals; D. grafted animals -t- TBP; â€¢¿.controls;O. controls + TBP. at this temperature. Nevertheless, the overall patterns remain similar, indicating an increase in prolactin binding in the grafted animals and a decrease as a result of TBP treatment.

E \ o DISCUSSION a. TBP is the frans isomer of broparestrol and is a powerful Z Ã- inhibitor of the development of mammary glands and of mam CJ mary carcinogenesis in female C3Hf (XVII) mice bearing a O transplanted pituitary under the kidney capsule. The inhibitions oc o. proceed through the depression of prolactin secretion. Studies of hormonal control by prolactin have been per ce formed on the liver (7, 21), rabbit mammary gland (11), 7,12- I- dimethylbenzanthracene-induced mammary tumors (10), and D murine mammary gland (36). We extended these studies to the C3Hf (XVII) experimental model and showed that the pituitary 65 90 115 DAYS TREATMENT isograft enhanced pituitary and serum prolactin concentration, along with an increase of specific binding of 125l-labeled bovine Chart 3. Effect of TBP treatment on pituitary prolactin concentration, grafted animals; D. grafted animals + TBP; â€¢¿,controls;O. controls + TBP. prolactin to mammary glands. TBP brought down the levels of

1676 CANCER RESEARCH VOL. 40

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1980 American Association for Cancer Research. Inhibition of Mammary Carcinogenesis in Mice circulating prolactin concurrent with reduced specific binding. is a depressor of serum prolactin by means of a hypothalamo- It thus appears that an increase in serum prolactin raises its pituitary inhibition (12), probably through its direct action on own specific binding to the target tissue and consequently the prolactin-inhibiting factor or on the prolactin-releasing fac increases mammary gland development and mammary carci- tor of the hypothalamus (6). nogenesis. Induction of prolactin receptors by prolactin itself in liver tissues has been demonstrated by transplanting a ACKNOWLEDGMENTS pituitary under the kidney capsule (27) or by exogenous treat ment with prolactin (7). It has been shown that low doses of We are highly indebted to National Institute of Arthritis, Metabolism, and Digestive Diseases, Bethesda, Md., for the gift of bovine prolactin; to Dr. Y. N. estrogens increase prolactin binding as well as pituitary and Sinha, Scripps Clinic and Research Foundation, La Jolla, Calif., for the radioim- serum prolactin (5, 36) and that ovariectomy causes a signifi munoassay kit of mouse prolactin; to C. Favier, LaRoche-Navarron Laboratories, cant decrease in prolactin binding to liver tissue (14). It is for the supply of the compound which we used; to F. Sangrado for her excellent histological help; and to L. Aussepe for his collaboration as animal technician. known that mammary growth and mammary carcinogenesis We wish to thank Dr. Y. N. Sinha and Dr. M. K. Schwartz for helpful discussion. are very susceptible to the hormonal environment, since most hormone-responsive mammary tumors in rodents appear to REFERENCES require the participation of both the pituitary glands and the ovaries for an optimal growth process. 1. Astwood, E. B. The regulation of corpus luteum function by hypophyseal luteotropin. Endocrinology, 29. 309-320, 1941. Our studies revealed that TBP treatment causes the atrophy 2. Behrman, H. R.. Orczyk, G. P.. MacDonald, G. J., and Creep, R. C. Prolactin of the ovaries associated with a reduced prolactin level, it has induction of enzymes controlling luteal cholesterol ester turnover. Endocri nology, 87: 1251-1256, 1970. been shown that treatment with several alkaloids leads to a 3. Boot, L. M. Prolactin and mammary carcinogenesis. The problem of human regression of the ovaries (4, 39, 48, 50). The significance of prolactin. Int. J. Cancer, 5. 167-175, 1970. such a regression remains unclear, although it has been sug 4. Carpent, G., and Desclin, L. Effects of ergocornine on the mechanism of gestation and on fetal morphology in the rat. Endocrinology, 84. 315-324, gested that this effect could be due to an inhibition of luteal 1969. activity by pituitary prolactin (45). 5. Chen, C. L., and Meites, J. Effects of estrogen and progesterone on serum It has been shown recently that concurrent treatment with and pituitary prolactin levels in ovariectomized rats. Endocrinology, 86: 503-505, 1970. TBP produced a strong inhibition of induced carcinogenesis of 6. Clemens. J. A., and Meites, J. Hypothalamic control of prolactin secretion. 7,12-dimethylbenzanthracene-treated Sprague-Dawley female In: B. A. Stoll (ed.). Mammary Cancer and Neuroendocrine Therapy, pp. rats. However, it was also observed that the ovaries of the 160-178. London: Butterworth & Co. Ltd.. 1974. 7. Costlow. M. E.. Buschow, R. A., and McGuire, W. L. Prolactin stimulation of females which were fed a normal diet contain a great number prolactin receptors in rat liver. Life Sci.. 17: 1457-1465. 1975. of large corpora lutea. No such structures developed in the 8. Danguy, A., Legros, N., Heuson-Stiennon, J. A.. Pasteeis. J. L., Atassi, G., and Heuson, J. C. Effects of a gonadotropin-releasing hormone (GnRH) ovaries of animals fed a diet containing 2 or 20 ppm of TBP analogue (A 43818) on 7,12-dimethylbenz(a)anthracene-induced rat mam (32). mary tumors. Eur. J. Cancer, 13: 1089-1094, 1977. It is possible that the cancer-inducing action of prolactin, as 9. Desclin, L. A propos du MÃ©canismed'action des oestrogÃ¨nes sur le lobe antÃ©rieurde l'hypophyse chez le rat. Ann. Endocrinol.. 7): 656-659. 1950 well as the inhibition obtained with antiprolactinic compounds, 10. De Sombre, E. R., Kledzik. G., Marshall, S., and Meites, J. Estrogen and proceed finally from the influence of this pituitary hormone on prolactin receptor concentration in rat mammary tumors and response to the secretions of the corpus luteum or on the inactivation of endocrine ablation. Cancer Res.. 36. 354-358. 1976. 11. Djiane, J., and Durand, P. Prolactin-progesterone antagonism in self-regu circulating progesterone. lation of prolaction receptors in the mammary gland. Nature (Lond.). 266 Astwood (1) was the first one to show in 1941 that, among 641-643, 1977. 12. Floss, H. G., Cassady, J. H., and Robbers, J. E. Influence of ergot alkaloids other functions, prolactin maintains the secretory activity of on pituitary prolactin and prolactin dependent processes. J. Pharm. Sci.. corpus luteum, and more recently, Behrman eÃal. (2) have 62. 699-715, 1973. 13. Frantz, W. L., and Turkington, R. Formation of biologically active '"l-prolac- established that prolactin promotes the secretion of progester tin by enzymatic radioiodination. Endocrinology. 97. 1545-1548. 1972. one. Swearingen and Nicoli (42) have shown that prolactin is 14. Gelato, M., Marshall, S.. Boudreau, M., Bruni. J., Campbell. G. A., and an inhibitor of the synthesis of the 20-a-hydroxysteroid dehy- Meites, J. Effect of thyroid and ovaries on prolactin binding activity in rat drogenase which converts progesterone into an inactive me liver. Endocrinology, 96. 1292-1296, 1975. 15. Harper, M. J. K.. and Walpole, A. L. Contrasting endocrine activities of cis tabolite, 20-a-hydroxy-4-pregnen-3-one. It can be postulated and trans isomers in a series of substituted triphenylethylenes. Nature that antiprolactinic compounds, such as TBP, favor the synthe (Lond.), 272. 87, 1966. sis of the enzyme, and accordingly inactivate progesterone. 16. Harper, M. J. K., and Walpole, A. L. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J. Reprod. FÃ©rtil., 73. These experiments have demonstrated that, at least in ro 101-119, 1967. dents, the presence or the absence of prolactin in the circula 17. Heuson, J. C.. Waelbroeck-Van Gaver, C., and Legros, N. Growth inhibition of rat mammary carcinoma and endocrine changes produced by 2-Br-o- tion plays an important role in induced mammary carcinogen ergocryptine. a suppressor of lactation and nidation. Eur. J. Cancer. 5: 353- esis of pituitary-transplanted mice or dimethylbenzanthracene- 356, 1970. treated rats. Furthermore, it is probable that this hormone 18. Kim. U., and Furth, J. Relation of mammary tumors to mammotropes. II. Hormone responsiveness of 3-methylcholanthrene induced mammary car intervenes also in the etiology of spontaneous mammary car cinomas. Proc. Soc. Exp. Biol. Med.. 703. 643-645, 1960. cinogenesis (40). 19. Kim. U.. Furth, J., and Clifton. K. H. Relation of mammary tumors to It has not yet been clearly established what mechanism mammotropes. Ml. Hormone responsiveness of transplanted mammary tu mors. Proc. Soc. Exp. Biol. Med.. 703. 646-650. 1960. makes prolactin a cancer-inducing agent. Several investiga 20. Lowry. O. H.. Rosebrough, N. J., Farr, A. L.. and Randall, R. J. Protein tions suggest that estrogen-induced cancers have to be attrib measurement with the Folin phenol reagent. J. Biol. Chem.. 793 265-275. uted to a rise of prolactin secretion after administration of the 1951. 21. Manni, A.. Chambers, M. J., and Pearson, O. H. Prolactin induces it own ovarian hormone (5, 18, 19). receptor in rat liver. Endocrinology. 703. 2168-21 71, 1978. Several chemical compounds, such as lysergide, u-dopa, 22. Montes-Rendon. A.. Rudali, G.. and Guggiari, M. Inhibition of the develop ment of the mammary gland of mice with a bromotriphenylethylene Biomed bromocryptine, pargyline, and others are inhibitors of mam Express (Paris). 29 276-279, 1978. mary carcinogenesis in rats. In nearly all cases, the chemical 23. MÃ¼ckter.H., Frankus. E., and More, E. Experimental investigations with 1-

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(morpholinomethyl)-4-phthalimÂ¡dopÂ¡peridÂ¡ndÂ¡one-2.6 and drostanolone pro- prolactin and other lactogenic hormones in mammary carcinoma cells. pionate in dimethylbenzanthracene-induced tumors of Sprague-Dawley rats. Science (Wash. D. C.), 180: 968-971, 1973. Cancer Res.. 30. 430-438. 1970. 38. Sinha, Y. N., Selby, F. W., Lewis, U. J., and Vander Laan, W. P. Studies of 24 Muhlbock, O., and Boot, L. M. Induction of mammary cancer in mice without prolactin secretion in mice by a homologous radioimmunoassay. Endocri the mammary tumor agent by isografts of hypophyses. Cancer Res.. 79. nology, 91: 1045-1053. 1972. 402-412, 1959. 39. Sinha. Y. N., Selby. F. W., and Vander Laan, W. P. Effects of ergot drugs on 25 Nagasawa. H.. and Meites. J. Suppression by ergocornine and iproniazid of prolactin and growth hormone secretion and on mammary nucleic acid carcinogen-induced mammary tumors in rats; effect on serum and pituitary content in C3H/BÃ• Mice. J. Nati. Cancer Inst., 52. 189-191. 1974. prolactin levels. Proc. Soc. Exp. Biol. Med.. 135: 469-472, 1970. 40. Sinha. Y. N., Selby. F. W., and Vander Laan. W. P. The natural history of 26. Pearson, O. H., Llerena, O., Llerena. L. Molina. A., and Butler, T. Prolactin- prolactin and GH secretion in mice with high and low incidence of mammary dependent rat mammary cancer: a model for man? Trans. Assoc. Am. tumors. Endocrinology, 94: 757-764, 1974. Physicians, 82. 225-238. 1969. 41. Stahelin, H.. Burckhardt-Vischer, B., and FlÃ¼ckiger,E. Rat mammary cancer 27. Posner, B. I., Kelly, P. A., and Friesen. H. G. Prolactin receptors in rat liver: inhibition by a prolactin suppressor, 2-bromo-a-ergocryptine (CB - 154). possible induction by prolactin. Science (Wash. D.C.), ÃŽ88:57-59. 1975. Experientia (Basel). 27. 915-916, 1971. 28. Powell, B. L.. Diamond. E. J., Koprak. S.. and Hollander. V. P. Prolactin 42. Swearingen, K. C.. and Nicoli, C. S. Functions of prolactin in vertebrates. In: binding in ovariectomy-responsive and ovariectomy-nonresponsive rat mam A. B. Stoll (ed.). Mammary Cancer and Neuroendocrine Therapy, pp. 229- mary carcinoma. Cancer Res.. 37: 1328-1332, 1977 245. London: Butterworth & Co. Ltd., 1974. 29. Quadri, S. K., Clark. J. L., and Meites, J. Effects of LSD, pargyline and 43. Sweeney, M. J., Poore, G. A.. Kornfeld. E. C.. Bach. N. J., Owen, N. V., and haloperidol on mammary tumors growth in rats. Proc. Soc. Exp. Biol. Med., Clemens, J. A. Activity of 6-methyl-8-substituted eroglines against the 7,12- 142: 22-26. 1973. dimethylbenz[a]anthracene-induced mammary carcinoma. Cancer Res., 35: 30. Quadri, S. K.. Kledzik, G. S., and Meites. J. Effects of L-dopa and methyl- 106-109, 1975. dopa on growth of mammary cancers in rats. Proc. Soc. Exp. Biol. Med., 44. Turkington, R. W. Prolactin receptors in mammary carcinoma cells. Cancer 142: 759-761. 1973. Res., 34: 758-763, 1974. 31. RÃ¶pcke. G. Interaction of hypophyseal isografts and ovarian hormones in 45. Valavudhi, P., Lobel, B. L., and Shelesnyak, M C. Studies on the mechanism mammary tumor development in mice. Thesis. Amsterdam: Mondeeloffset- of nidation. XXIII. Effect of ergocornine in pregnant rats during experimen drukkery, Amsterdam, 1975. tally induced delayed nidation. J. Endocrinol., 430. 425-430. 1966. 32. Rudali, G.. Montes-Rendon. A., and Assa, R. Inhibition of mammary carci- 46. Welsch, C. W., and Meites, J. Effects of reserpine on development of 7,12- nogenesis of dimethylbenzanthracene treated rats with a brominated tri- dimethylbenzanthracene-induced mammary tumors in female rats. Experien phenylethylene. Biomedicine (Paris), 31: 142-146, 1979. tia (Basel), 26. 1133-1134, 1970. 33. Rudali. G.. Montes-Rendon. A., and Guggiari. M. Inhibition de la cancero- 47. Welsch, C. W., and Nagasawa, H. Prolactin and murine mammary carcino- genÃ¨se mammaire de souris C3H/f Ã l'aide du broparestrol. C. R. Soc. Biol.. genesis: a review. Cancer Res.. 37. 951-963. 1977. )72. 845-849. 1978. 48. Yanai, R., and Nagasawa. H. Suppression of mammary hyperplastic nodule 34. Sakai. S., Enami, J., Mandi. S., and Banerjee, M. R. Prolactin receptor on formation and pituitary prolactin secretion in mice induced by ergocornine dissociated mammary epithelial cells at different stages of development. or 2-bromo-a-ergocryptine. J. Nati. Cancer Inst.. 45: 1105-1112, 1970. Mol. Cell Endocrinol.. 12: 285-298. 1978. 49 Yanai. R., and Nagasawa. H. Inhibition of mammary tumorigenesis by ergot 35. Scatchard. G. The attraction of proteins for small molecules and ions. Ann. alkaloids and promotion of tumorigenesis by pituitary isografts in adreno- N. Y. Acad. Sci.. 51: 660-672. 1949. ovariectomized mice. J. Nati. Cancer Inst., 48: 715-719, 1972. 36. Sheth. N. A.. Tikekar, S. S., Ranadive, K. J., and Sheth. A. R. Influence of 50 Zeilmaler. G. H., and Carlsen, R. A. Experimental studies on the effect of bromoergocryptine on estrogen modulated prolactin receptors of mouse ergocornine methanesulfonate on the luteotrophic function of the rat pituitary mammary gland. Mol. Cell Endocrinol., 12: 167-176, 1978. gland. Acta Endocrinol.. 41: 321-335, 1962. 37. Shiu, R. P. C., Kelly, P. A., and Friesen. J. G. Radioreceptors assay for

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Figs. 1 to 4. Mammary glands of 75-day-old C3Hf (XVII) females which bore a pituitary isograft during 50 days, x 18. Fig. 1. Control without treatment. Fig. 2. Female on a 2-ppm TBP diet for 50 days. Fig. 3. Female on a 20-ppm TBP diet for 50 days. Fig. 4. Female on a 200-ppm TBP diet for 50 days.

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1980 American Association for Cancer Research. Inhibition of Prolactin-induced Mammary Cancer in C3Hf (XVII) Mice with the trans Isomer of Bromotriphenylethylene

Michel Drosdowsky, Marc Edery, Michèle Guggiari, et al.

Cancer Res 1980;40:1674-1679.

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