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The Molecular Biology of RU486. Is There a Role for Antiprogestins in the Treatment of Breast Cancer?*

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The Molecular Biology of RU486. Is There a Role for Antiprogestins in the Treatment of Breast Cancer?* 0163-769X/92/1302-0146$03.00/0 Endocrine Reviews Vol. 13, No. 2 Copyright 0 1992 by The Endocrine Society Printed in U.S.A. The Molecular Biology of RU486. Is There a Role for Antiprogestins in the Treatment of Breast Cancer?* KATHRYN B. HORWITZ DeDartments of Medicine and Patholot!v. Universitv of Colorado Health Sciences Center, Division of Endocrinology,. Denuer, Colorado 8026~ ’ I. Introduction spread use of tamoxifen reflects its efficacy and low II. Progesterone and the Normal Breast toxicity, and the fact that it makes good physiological III. Progesterone and Breast Cancer sense to block the local proliferative effects of estrogens A. Progestin agonists and tumor induction directly at the breast. But are estrogens the only hor- B. Progestin agonists and growth of established tumors mones with a proliferative impact on the breast and on IV. Molecular Mechanisms of Progesterone Antagonists A. Progesterone receptors breast cancers? This review focuses on evidence that B. Molecular mechanisms of progesterone antagonists progesterone also has proliferative actions in the breast; 1. Affinity for inactive PR - on the role of synthetic progestins in breast cancer 2. PR activation treatment; on the molecular biology of progesterone an- 3. DNA binding tagonists; and on the preliminary data showing that 4. Dimerization progesterone antagonists may be powerful new tools for 5. Transcription the management of metastatic breast cancer, because 6. PR “processing” or down-regulation they block the local effects of endogenous progesterone V. Progesterone Antagonists and the Treatment of Breast on breast cell proliferation. The reader is also referred Cancer to the excellent general review on progestin regulation A. Human breast cancer cell lines B. Animal models of mammary cancer of cell proliferation by Clarke and Sutherland (1). The C. Human clinical trials structures of the agonists and antagonists discussed in VI. Progestin Resistance this review are shown in Fig. 1. VII. Summary and Future Prospects I. Introduction II. Progesterone and the Normal Breast NDOCRINE therapy used either prophylactically Conventional wisdom holds that the mechanisms by E or therapeutically for the treatment of locally ad- which estradiol and progesterone regulate the prolifera- vanced or metastatic breast cancers offers many advan- tion and differentiation of uterine epithelial cells apply tages to patients whose tumors contain functional estro- equally to the breast. This is probably inaccurate (2-4). gen and progesterone receptors (ER and PR). The range In the uterus, estrogens are clearly mitogenic, and addi- of treatments defined as endocrine include surgical abla- tion of progesterone to the estrogenized endometrium tion of endocrine glands, administration of pharmacolog- leads to the appearance of a secretory pattern character- ical doses of steroid hormones, chemical blockade of ized by cells engaged in protein synthesis rather than steroid hormone biosynthesis, and inhibition of endoge- cell division (5). That is, in the uterus, estradiol is a nous steroid hormone action at the tumor with synthetic proliferative hormone; progesterone is a differentiating antagonists. The last of these approaches is the most hormone. For this reason the unopposed actions of estra- widely used, making the antiestrogen tamoxifen the pre- diol are considered to be tumorigenic in the uterus, while ferred first-line therapeutic agent for treatment of hor- the risk of endometrial hyperplasia and cancer is lowered mone-dependent metastatic breast cancer. The wide- when estrogens are combined with progestins. In fact, the combined regimen may even be protective since a Address requests for reprints to: Kathryn B. Horwitz, Ph.D., Divi- decrease in endometrial cancers has been reported in sion of Endocrinology, Box B151, University of Colorado Health Sci- women prescribed combined estrogens and progestins, ences Center, 4200 East Ninth Avenue, Denver, Colorado 80262. *Supported in part by grants from the National Cancer Institute compared to women receiving no treatment (Ref. 6 and and the American Cancer Society. references therein). 146 Downloaded from edrv.endojournals.org on February 27, 2005 May, 1992 RU486 AND BREAST CANCER FIG. 1. The structure of progesterone, the synthetic progestin agonist R5020, and four progesterone antagonists dis- cussed in this review. However, considerable evidence has now accrued to progestin components of oral contraceptives increase the suggest that in the epithelium of the breast, progesterone thymidine labeling index with progestin-only formula- has a different influence. That, like estradiol, progester- tions exhibiting high activity (2-4). The investigators one in the breast has a strong proliferative effect. Studies conclude that it is difficult to sustain the idea that in support of this come both from experimental models progestins are protective in the breast (3). It would seem and from normal cycling women. Both the proliferation that more work must be done to understand the actions of normal mammary epithelium in virgin mice and the of progestins in the normal breast, but that clinical lobular-alveolar development of mammary tissues in decisions based on an inappropriate uterine model sys- pregnant mice require progesterone (7,8). A fundamental tem are unjustified (14). difference in the actions of estradiol and progesterone in the breast is that the latter stimulates DNA synthesis, III. Progesterone and Breast Cancer not only in the epithelium of the terminal bud, but also A discussion of the role of progestins in breast cancer in the ductal epithelium (9). The stimulating effects of must distinguish between their effects on carcinogenesis progesterone on the development of mammary gland and their role in regulating proliferation of established buds can be inhibited by progesterone antagonists (10). cancers. Data from normal human mammary cells have been more difficult to obtain and are often equivocal. Com- A. Progestin agonists and tumor induction pared to the increase caused by estradiol treatment (11.3- fold), progesterone treatment only marginally (2.0-fold) Progestin agonists have been shown to be carcinogenic increases the mitotic index of normal human breast or to increase the incidence of spontaneous mammary ductal epithelium maintained in intact athymic nude tumors in dogs and mice (E-19). In mice, results vary mice (11). In fact, Mauvais-Jarvis and colleagues (12, 13) with the strain tested, suggesting the contribution of a concluded, using primary cultures of epithelial cells from genetic component; however, tumorigenic effects of pro- normal human mammary glands, that while estradiol gestins have been observed whether or not the strain treatment stimulates growth, progestins inhibit growth. harbors the mouse mammary tumor virus (MMTV). The Their data are difficult to interpret, however, since the importance of progesterone in carcinogen-induced rat experiments using estradiol were done with cells growing mammary cancers is documented by the early reports of in minimally supplemented medium, while the progestin Huggins et al. (20-22), who showed that pregnancy pro- treatment studies were done with cells in optimally sup- motes the growth of dimethylbenzanthracene (DMBA)- plemented medium, and any progestin growth-stimula- induced mammary tumors, and that administration of tory effect might have been masked. In contrast to the progesterone together with the carcinogen to intact rats sparse and conflicting in. vitro data are studies of the accelerates the appearance of tumors, increases the num- mitotic rate in breast epithelial cells during the normal ber of tumors, and augments the growth rate of estab- menstrual cycle and in women taking oral contraceptives. lished tumors. The relationship between progestins and These data show that the highest thymidine labeling carcinogenesis is temporally complex. In general, proges- indices occur during the progestin-dominated, secretory terone administered simultaneously with, or after, the phase of the menstrual cycle. Both the estrogen and the carcinogen enhances tumorigenesis, while progesterone Downloaded from edrv.endojournals.org on February 27, 2005 148 HORWITZ Vol. 13. No. 2 given before the carcinogen inhibits tumorigenesis (Ref. that progestin-sensitive cells can generate resistant sub- 23 and references therein). Thus, the high progesterone populations (48); and it is possible that no physiological levels associated with pregnancy can be protective if the consensus is likely to be forthcoming using these in vitro hormone precedes administration of the carcinogen (24). models. These models remain invaluable, however, for Extrapolation of these experimental models to human the analysis of molecular mechanisms of progestin ac- disease is unclear since the only data available for the tions, and to underscore the complexities inherent in latter are epidemiological in nature and relate hormone tumor cell biology. use, particularly oral contraceptive use, to the risk of Where does this leave us on the critical issue of the breast cancer. The trend toward increased risk with use of progestin agonists in breast cancer treatment? increased duration of hormone use appears repeatedly Interestingly, here there is more agreement, but the data (25, 26), and a possible adverse effect of progestins ap- contradict the conclusion that physiological levels of pears to be likely (27, 28). This is discouraging when progestins are growth stimulatory. Especially at high taken together
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