Selective Estrogen Receptor Modulation: a Personal Perspective1

[CANCER RESEARCH 61, 5683–5687, August 1, 2001] Perspectives in Cancer Research

Selective Estrogen Receptor Modulation: A Personal Perspective1

V. Craig Jordan2 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611

Introduction and Walpole (12), was a potent estrogen antagonist with antifertility properties in animals. Fortunately, Walpole was interested in the Professor Paul Ehrlich is the father of experimental chemotherapy. experimental chemotherapy of cancer (13) and patented one of the During the first decade of the 20th Century, he reasoned that com- potential applications of ICI 46,474 as a treatment of hormone- pounds could be synthesized to exhibit selective toxicity on a parasite dependent cancers (14). without affecting the host. The synthesis, laboratory evaluation, and Subsequently, preliminary clinical studies in advanced breast can- clinical development of Salvarsan, the 606th compound tested, revo- cer showed some activity (15, 16), but ICI 46,474, or tamoxifen as it lutionized the treatment of syphilis, which was at the time a massive became known, was only as effective as the standard endocrine and certain killer (1, 2). The key to success was the notion that a therapy at the time diethylstilbestrol (17). The key to additional receptor, present only in the parasite, was the target. More impor- advances was the findings that (a) there were few side effects (15–17), tantly, the development of the first successful synthetic therapy for an and (b) the ER was a suitable target for patient selection (18–20). infectious disease also established a logical approach to the design of all subsequent chemotherapies. Clinical Evaluation of Tamoxifen Ehrlich also turned his attention to cancer. His fame was such that this alone evoked statements in the media such as, “The beginning of the end Progress in the strategic use of endocrine therapy for breast cancer of the cancer problem is in sight,” and by 1912, the Scientific American has occurred through the close cooperation between the laboratory stated “unquestionably their investigations justify the hopes of a cure of and the clinic. The laboratory principles that tamoxifen would benefit human cancer” (3). However, in 1915, Ehrlich declared, “I have wasted ER-positive patients (18–20), long-term adjuvant therapy would be 15 years of my life in experimental cancer” (3). The Nobel Laureate, Paul more effective than short-term therapy (21, 22), and tamoxifen could Ehrlich, died on August 20, 1915, at the age of sixty-one. increase the incidence of endometrial cancer (23, 24) have all trans- A cure for cancer remained elusive throughout the 20th Century, lated effectively to the clinic (25). It is estimated that there are but Ehrlich’s legacy is the demonstration of a logical approach to a 400,000 women alive today because of long-term adjuvant tamoxifen complex problem: identify a selective target, identify a drug in the treatment (14). This fact is partially responsible for the decreasing laboratory, test the drug on experimental disease, and conduct clinical death rates from breast cancer observed during the past decade in the studies. On the basis of this process and of a change in the philosophy United States and United Kingdom (26). of treating not just late disease but early disease with adjuvant therapy, However, tamoxifen is more than a treatment for breast cancer. On progress has been made in the past 30 years that can now be quanti- the basis of laboratory studies that showed tamoxifen could prevent tated. In addition, there has been a conceptual shift to use chemother- rat mammary carcinogenesis (27, 28) and the of clinical finding that apy (used in the context of Ehrlich’s definition) as a chemopreventive tamoxifen prevented contralateral breast cancer (29), the worth of (4, 5). This has resulted in a paradigm shift to consider SERMs3 as tamoxifen was tested successfully to reduce the incidence of breast multifunctional medicines (6, 7). cancer in high-risk women (30). Tamoxifen is the first chemopreventive to be available to reduce the incidence of breast cancer in pre- and postmenopausal high-risk women. Breast Cancer

Some breast cancers are known to be responsive to estrogen for The Properties of a SERM growth. However, the identification of the ER as the mediator for Progress in developing tamoxifen for chemoprevention depended estrogen action in estrogen-targeted tissues in laboratory animals (8, on the recognition of the unique properties of nonsteroidal anti- 9) and the development of the ER assay by Jensen to identify breast estrogens. Clearly, if antiestrogens are to be used in well women, and cancer patients whose tumor would be responsive to endocrine ther- estrogen is necessary to prevent osteoporosis and CHD, then tamox- apy (10) also provide a suitable target for chemotherapy (used in ifen could prevent breast cancer but increase the risk of death caused Ehrlich’s context). The first nonsteroidal antiestrogen, MER 25 (11), by osteoporosis and CHD. However, the recognition that tamoxifen was too toxic and of low potency, but ICI 46,474, described by Harper was a SERM in the laboratory i.e., produced estrogen-like or antiestrogenic effects at different target tissues (24, 31) was pivotal to Received 4/25/01; accepted 5/30/01. advance the use of tamoxifen in well women. Tamoxifen maintained The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with bone density in rats (32–34), and this translated to improved bone 18 U.S.C. Section 1734 solely to indicate this fact. density (35, 36) and a statistically nonsignificant reduction in fractures 1 Supported by the Lynn Sage Foundation of Northwestern Memorial Hospital; Avon in postmenopausal women (30). However, it was clear that tamoxifen Products Foundation; and National Cancer Institute Grants RO1 CA 56143 and Special- ized Program of Research Excellence in Breast Cancer P50 CA 89018. Presented at a could not be used widely in well women without elevated risk factors symposium for the 24th Annual Bristol-Myers Squibb Award for Distinguished Achieve- for breast cancer. A new approach was necessary to exploit the ment in Cancer Research, April 10, 2001. properties of SERMs and reduce the risk of breast cancer in the 2 To whom requests for reprints should be addressed, at Robert H. Lurie Comprehen- sive Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, general postmenopausal population. Olson Pavilion 8258, Chicago, IL 60611. Phone: (312) 908-4148; Fax: (312) 908-1372; The laboratory and preliminary clinical finds in the 1980s lead to a E-mail: [email protected]. 3 The abbreviations used are: SERM, selective ER modulator; ER, estrogen receptor; paradigm shift in chemopreventive strategies that was simply stated as CHD, coronary heart disease; AF, activating function. follows (6): “We have obtained valuable clinical information about 5683

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2001 American Association for Cancer Research. SERMs: A PERSONAL PERSPECTIVE this group of drugs that can be applied in other disease states. Research does not travel straight lines, and observations in one field of science often become major discoveries in another. Important clues have been garnered about the effects of tamoxifen on bone and lipids so it is possible that derivatives could find targeted applications to retard osteoporosis or atherosclerosis. The ubiquitous application of novel compounds to prevent diseases associated with the progressive changes after menopause may, as a side effect, significantly retard the development of breast cancer. The target population would be postmenopausal women in general, thereby avoiding the requirement to select a high-risk group to prevent breast cancer.” The result is raloxifene. Raloxifene (formerly known as LY156,758 or keoxifene) has only weak estrogen-like properties in the rodent uterus (37) but preserves bones in ovariectomized rats (32), prevents rat mammary carcinogenesis at high doses (38), and appears to have reduced activity as a growth stimulator in an experimental model of endometrial cancer (39). Raloxifene has been shown to reduce fractures in women at risk for osteoporosis (40) and to decrease circulat- ing cholesterol (41). Most importantly, raloxifene decreases the incidence of breast cancer (42) and has no estrogen-like action on the uterus (43, 44). Raloxifene is available for the treatment and prevention of osteoporosis and is being tested as a preventive for CHD and breast cancer in selected populations of high-risk postmenopausal women (45). There is currently enormous interest in developing new SERMs as multifunctional medicines (7, 46). Progress is being facilitated by the elucidation of the complexity of SERM action at the subcellular level. Although it is fair to say that a complete picture for each target site is not known, advances have been made during the past decade that will provide new targets for future endeavors.

Decisions for a SERM to Modulate Genes Fig. 1. Decision points that a SERM must pass to modulate estrogen-like actions in a target tissue. A SERM can bind to either ER␣ or ER␤, and the complexes can then recruit coactivators or corepressors. The complexes may homo- or heterodimerize and modulate There are a number of decision points that ultimately will determine genes by either a nontraditional pathway of protein-protein interactions or a traditional the biological response to a SERM (Fig. 1). There are two structurally pathway of ER-DNA interaction. related ERs, referred to as ER␣ and ER␤ (47), that have some degree of homology with each other. A SERM, therefore, has a choice of receptor molecules. Both ERs have a ligand binding and a DNA tamoxifen resistance, the chance finding of a D351Y ER mutation in binding domain, and can directly bind to DNA to activate gene a tamoxifen-stimulated breast tumor (52), that enhanced the estrogen- transcription. There are, however, differences in the AFs that can alter like actions of SERMs (53–55), was an invaluable starting point to the SERM-ER complex, resulting in increased or decreased estroge- decipher how SERMs modulate ER function. The change in biology nicity. Tamoxifen appears to be more antiestrogenic when complexed produced by the mutant ER has subsequently been supported by X-ray with ER␤, compared with ER␣ (48). It is now clear that the ligand crystallography (56–58). programs the shape of the ER complex (49) so that coactivators or It is now known that the antiestrogenic side chain of a SERM corepressors can bind to the external surface of a SERM-ER complex interacts differently with the surface amino acid D351. The structure- (50). Coactivators will aid signal transduction, whereas corepressors function relationships of ER␣ can be examined by stable transfection will block transduction. At the time that a transcriptional complex is of mutant ERs into ER-negative breast cancer cells using TGF␣ as a to be formed, the SERM-ER␣␤ complexes must decide whether to target gene in situ to evaluate the estrogenicity of SERMs (53, 54, 59). homo- or heterodimerize, before initiating gene transcription. Lastly, The aspartate at amino acid 351 of ER␣ is important for the interac- there is evidence to suggest that SERMs can modulate gene transcription of the antiestrogenic side chains of SERMs and is critical to tion through two distinct mechanisms, either an activating protein-1 regulate SERM programming (56, 57, 60). The surface charge of pathway, when a protein-protein interaction occurs with fos and jun, D351 is not neutralized or shielded by the side chain of 4-hydroxy- or the SERM-ER complex can activate or silence an estrogen response tamoxifen; therefore, in a coactivator-rich environment, these proteins element directly on DNA (51). may bind to the SERM-ER complex to initiate TGF␣ gene transcrip- At this point, it is not possible to describe all of the mechanisms of tion. In contrast, the side chain of raloxifene shields the surface amino SERMs at a target site because the proportions of ERs, coregulator acid D351 and produces only an antiestrogenic complex at the TGF␣ proteins, and pathways at different sites have not been established. gene target. The hypothesis to explain the enhanced estrogen-like However, it is possible to describe the modulation of ER␣ by SERMs action of 4-hydroxytamoxifen has been tested by interrogating the under precise laboratory conditions. SERM-ER complex. The substitution of a noncharged amino acid at In the early 1990s, it was believed that drug resistance to tamoxifen position 351 (e.g., glycine) silences the estrogen-like action of the occurred through mutation of the ER. This would change the phar- 4-hydroxytamoxifen-ER complex (61). This observation is consistent macology of an antiestrogen to an estrogen. Although it is now clear with the idea that the 4-hydroxytamoxifen-ER complex must bind that mutations of the ER are not responsible for the development of coactivators at a novel site other than the traditional AF-2 site, which 5684

Fig. 2. The modulation of the ER␣ complex by interaction of the antiestrogenic side chain of SERMs with surface amino acid D351. Data adapted from X-ray crystallography and the biology of complexes. is blocked by helix 12 in the 4-hydroxytamoxifen-ER complex (57). concept (36) encouraged the development of raloxifene for the pre- The new activating site for coactivator binding on the SERM-ER vention of osteoporosis. Now, numerous new SERMs (63, 64, 70–73) complex is called AF-2b (61), which is distinct from the coactivator are being evaluated as multifunctional medicines. binding site AF-2 used by estrogens in the ligand binding domain The concept that selective compounds (such as SERMs) can en- (57). Additionally, changing the side chain of 4-hydroxytamoxifen to hance or repress signal transduction through the ER is now being that of GW 7604 with a carboxylic acid has been found to repel the advanced further with an evaluation of the selective androgen receptor aspartate at 351 and silence estrogen action in the complex (62). The modulators for the androgen receptor (74, 75), selective aryl hydro- compound GW 7604 is the active metabolite of the tamoxifen ana- carbon receptor modulators for the aryl hydrocarbon receptor (76), logue GW 5638 (63), which apparently has potential for the treatment selective peroxisome proliferator-activated receptor modulators for of breast cancer (64). Lastly, the raloxifene-ER complex can be made the peroxisome proliferator-activated receptor ␥ (77), and selective more estrogen-like by substituting a bigger negatively charged amino thyroid receptor modulators for the thyroid receptor (78). The general acid, such as tyrosine-351 (65). Thus, the estrogen-like action of applicability of modulating multiple receptors, or indeed orphan re- SERMs is controlled through an interaction with a surface amino acid ceptors, holds the promise of treating and preventing diseases that at 351. Fig. 2 summarizes the recent literature on the SERM-ER␣ were beyond intervention a decade ago. complex. Remarkably, the crystallization of the pure antiestrogen ICI Acknowledgments 164,384 with ER␤ (66) shows that the antiestrogenic side chain follows the same path in the ER complex as the side chain of Dr. Jordan is the Diana, Princess of Wales Professor of Cancer Research. raloxifene (58). To do this, the steroid must flip over 180° in the This article is dedicated to the staff, students, and fellows in my laboratory, ligand binding domain. This maneuver had been predicted previously whose persistent efforts for more than 30 years have turned ideas into im- (67). The difference between a SERM and a pure antiestrogen is that proved health care. the AF-2b region on the surface of the ER is now disrupted by the antiestrogenic side chain and programmed for early destruction (68, References 69) via an intact helix 12 (65). 1. Marquardt, M. Paul Ehrlich. Berlin: Springer-Verlag, 1951. 2. Baumler, E. Paul Ehrlich, Scientist for Life, p. 288. New York: Holmes & Meier, Opportunities in “Chemotherapy” 1984. 3. Schrek, R. Fashions in cancer research. In: The Year Book of Pathology and Clinical Pathology, pp. 26–39. Chicago: The Year Book Publishers, 1959. The essence of Professor Paul Erhlich’s therapeutic strategy was to 4. Sporn, M. B., Dunlop, N. M., Newton, D. L., and Smith, J. M. Prevention of chemical develop chemotherapy that would kill the target cell and not affect the carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed. Proc., 35: host. The development of tamoxifen followed Erhlich’s method of 1332–1338, 1976. 5. Sporn, M. B. Approaches to prevention of epithelial cancer during the preneoplastic translating laboratory findings in model systems to aid patients. But, period. Cancer Res., 36: 2699–2702, 1976. tamoxifen provided a greater insight into drug action and has opened 6. Lerner, L. J., and Jordan, V. C. Development of antiestrogens and their use in breast the door to new opportunities. The recognition that the tamoxifen-ER cancer: eighth Cain memorial award lecture. Cancer Res., 50: 4177–4189, 1990. 7. Jordan, V. C. Designer estrogens. Sci. Am., 279: 60–67, 1998. complex can have either antiestrogenic or estrogenic actions at dif- 8. Jensen, E. V., and Jacobson, H. I. Basic guides to the mechanism of estrogen action. ferent targets (31) and the clinical proof of principle of the SERM Recent Prog. Horm. Res., 18: 387–414, 1962. 5685

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