Defining the "S" in SERMs

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Science  29 Mar 2002:
Vol. 295, Issue 5564, pp. 2380-2381
DOI: 10.1126/science.1070442

Successful treatment of hormone-responsive breast cancer [HN1] with the drug tamoxifen [HN2] represents a major accomplishment for cancer chemotherapy. Tamoxifen, which opposes the action of estrogen in certain tissues and mimics the action of this hormone in others, has been an important contributor to the decline in breast cancer mortality rates during the past decade. In the first significant demonstration of cancer chemoprevention [HN3], women at high risk of breast cancer who take tamoxifen or a related drug, raloxifene [HN4], halve their risk of developing the disease (1, 2). But despite its effectiveness in blocking estrogen action in the breast, tamoxifen has an Achilles heel—it stimulates proliferation of endometrial cells in the uterus, putting women who take it at a somewhat increased risk of developing endometrial cancer [HN5]. Shang and Brown [HN6], reporting on page 2465 of this issue (3), bring new insight to this conundrum. They reveal that the contradictory action of tamoxifen in the breast and uterus depends on a combinatorial collaboration between its binding partner, the estrogen receptor [HN7], and a specific cellular coregulatory protein, which acts on target genes in uterine cells.

Originally called antiestrogens, tamoxifen and raloxifene are better termed selective estrogen receptor modulators (SERMs) [HN8]. This term appropriately indicates that these compounds are not uniformly estrogen antagonists. Rather, they display an unusual tissue-selective pharmacology: They are agonists in some tissues (bone, liver, and the cardiovascular system), antagonists in other tissues (brain and breast), and mixed agonists/antagonists [HN9] in the uterus. Tamoxifen has greater uterine-stimulatory activity than raloxifene (46). Great efforts are under way to improve the tissue selectivity of SERMs so that they are optimized for preventing and treating breast cancer and for alleviating the symptoms of menopause.

It is now appreciated that the pharmacology of estrogens [HN10] is tripartite, relying not just on the ligand and estrogen receptor but also on third parties, such as gene promoter elements and coregulatory proteins (7). Crystal structures of the estrogen receptor bound to different ligands [HN11] (estrogen, tamoxifen, or raloxifene) reveal that ligands of different sizes and shapes induce a spectrum of receptor conformational states (8, 9). These states are then “interpreted” by the cellular complexion of coregulators and the environment of the local promoter of the target gene.

The estrogen receptor is a versatile transcriptional regulator and can interact with target genes, either by binding directly to DNA response elements or through indirect tethering to other DNA binding transcription factors. Coregulator proteins, which may be general or receptor specific (10, 11), are recruited to the receptor in a ligand-dependent manner. Such coregulator proteins include coactivators, which enhance transcription, and corepressors, which reduce transcription [HN12] (see the figure) (12, 13). With all of these partners, there would appear to be numerous combinatorial possibilities for achieving tissue-specific and gene-specific regulation by SERMs. Yet the specific molecular partners responsible for the differential stimulatory activity of tamoxifen and raloxifene in the uterus compared with their antagonism in the breast have not been identified.

SERMs in the spotlight.

The selective actions of SERMs (selective estrogen receptor modulators) in different tissues result from a combinatorial collaboration among several factors. Estradiol, an estrogen, or specific SERMs, such as tamoxifen or raloxifene, all bind to the estrogen receptor, inducing distinctly different receptor conformations. These different receptor conformations then interact with the regulatory sequences of target genes in different ways (for example, direct DNA interaction versus tethering to other transcription factors). The type of interaction and the cellular levels of coregulator proteins (coactivators or corepressors) determine the distinct patterns of coregulator recruitment to the ligand-receptor-gene assembly. In this way, either stimulation or inhibition of specific biological effects is elicited.

Shang and Brown identify the coactivators and corepressors that are recruited by the estrogen receptor to several target genes in breast and uterine cancer cells, in the presence of either the estrogen estradiol [HN13] or the SERMs tamoxifen and raloxifene. In both uterine and breast cancer cells, at genes where the estrogen receptor interacts directly with DNA, estradiol recruited coactivators, and both SERMs recruited corepressors. In addition, estradiol and raloxifene dictated the same pattern of coregulator recruitment at genes where the estrogen receptor becomes tethered to other transcription factors. Remarkably, however, in uterine cells where tamoxifen is an estrogen agonist, this SERM recruited coactivators rather than corepressors to gene sites where the estrogen receptor works by tethering. In contrast, tamoxifen recruited corepressors to the same gene sites in breast cancer cells, where it acts as an estrogen antagonist. The authors further show that the agonism of tamoxifen could be attributed specifically to the coactivator SRC1 [HN14], which is present at a higher level in uterine cells than in mammary gland cells. Thus, the stimulatory (agonistic) activity of tamoxifen in the uterus depends on three critical features: the conformation of the tamoxifen-receptor complex, the promoter context (tethered interaction versus direct DNA binding of the estrogen receptor), and the availability of a specific coactivator (SRC1) (see the figure).

Although the Shang and Brown study greatly advances our understanding of the molecular basis for the differential tissue- and gene-selective activities of SERMs, it also raises important mechanistic and medical issues. Despite the existence of numerous cellular coregulators, there is already considerable evidence for their tissue-selective and functionally distinct activities (1416). This is consistent with the finding that tamoxifen agonism in uterine cells is specifically dependent on higher amounts of SRC1 in this tissue. Will differential recruitment of coactivators to the estrogen receptor-tamoxifen complex in uterine cells, at gene sites where the estrogen receptor is tethered rather than bound directly, prove to be a general phenomenon, applicable to cells in other tissues where tamoxifen is an estrogen agonist? Will these observations made in cancer cells also hold true for normal cells? What is the part played in SERM selectivity by estrogen receptor β, the other receptor subtype found in many breast cancers and estrogen target tissues? Tamoxifen is effective in the treatment of breast cancer, yet tamoxifen resistance [HN15]—which is in fact a manifestation of increased tamoxifen agonism—often develops and compromises treatment (17, 18). Is this resistance attributable to changes in the level or activity of coregulators, such that the receptor-tamoxifen complex more effectively recruits certain coactivators or fails to recruit corepressors?

Our understanding of the molecular partners involved in the cell- and gene-selective activity of tamoxifen and raloxifene, advanced by the Shang and Brown study, provides a foundation for the development of SERMs that are optimized for breast cancer prevention and treatment and menopausal hormone replacement. In addition, similar approaches based on an appreciation of the combinatorial collaboration of compound, conformation, context, and coregulators should be of value in developing selective analogs of hormone ligands that bind to other nuclear receptors, such as SPRMs (progestins), SARMs (androgens), SGRMs (glucocorticoids), and SPARMs (peroxisome proliferator-activated receptor ligands) (19).

HyperNotes Related Resources on the World Wide Web

General Hypernotes

Dictionaries and Glossaries

The On-line Medical Dictionary is provided by CancerWeb.

InteliHealth makes available the Merriam-Webster Medical Dictionary.

The Medical Dictionary is provided by the MedicineNet Web site.

A cancer dictionary is provided by the National Cancer Institute (NCI).

A glossary of terms and symbols used in pharmacology is made available by the Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine.

Web Collections, References, and Resource Lists

The Google Web Directory provides links to Internet resources in biochemistry, cell biology, and pharmacology.

Biological Servers on the Web is provided by Atelier BioInformatique, Marseille, France. A collection of links to guides and tutorials in biology is included.

HealthWeb, a collaborative project of health sciences libraries, offers annotated listings of evaluated Internet resources.

MEDLINEplus, a resource maintained by the U.S. National Library of Medicine, provides links to Internet biomedical resources. Links to breast cancer and uterine cancer resources are provided.

The library of the Karolinska Institutet, Stockholm, provides links to biomedical information resources and services on the Internet. A collection of links to cancer resources is included.

The Guide to Internet Resources for Cancer is maintained by S. Cotterill, Faculty of Medicine Computing Center, University of Newcastle, UK.

OncoLink is a cancer information resource provided by the University of Pennsylvania Cancer Center.

The NCI's Web site provides information about cancer, clinical trails, and cancer research programs, as well as a collection of links to Internet resources related to cancer.

The Virtual Pharmacy Center is provided by Martindale's Health Science Guide.

Online Texts and Lecture Notes

Molecular Models for Biochemistry is a resource maintained by W. McClure, Department of Biological Sciences, Carnegie-Mellon University.

The Online Biology Book is provided by M. Farabee, Estrella Mountain Community College, Avondale, AZ.

J. Kimball maintains Kimball's Biology Pages, an online biology textbook and glossary.

The NCI's Science behind the News offers a presentation titled “Understanding estrogen receptors, tamoxifen, and raloxifene.”

Medical Biochemistry is a Web tutorial offered by the Department of Biochemistry and Molecular Biology at the University of Kansas Medical Center.

The Medical Biochemistry Page is provided by M. King, Terre Haute Center for Medical Education, Indiana University.

Medical Pharmacology and Disease-Based Integrated Instruction is a Web instructional resource provided by M. Gordon, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas School of Medicine.

C. Rinehart, Department of Biology, Western Kentucky University, provides lecture notes for a course on molecular and cellular biology.

General Reports and Articles

The September 1996 issue of Scientific American was a special issue on cancer.

The 1 October 1999 issue of Cancer Research had an article titled “Prevention of cancer in the next millennium,” which is the report of the Chemoprevention Working Group to the American Association for Cancer Research.

The summer 1999 issue of the Harvard Public Health Review had an article about tamoxifen by A. Benis titled “A prescription for prevention?”

The 16 October 1999 issue of Science News had an article by D. Christensen titled “Designer estrogens: Getting all the benefits, few of the risks.”

Volume 949 of the Annals of the New York Academy of Sciences, published December 2001, was titled Selective Estrogen Receptor Modulators (SERMS). (Open access to the Annals full text will be available through June 2002.)

The 1 February 2002 issue of Science had a review article by A. Brivanlou and J. Darnell Jr. titled “Signal transduction and the control of gene expression.” The 17 March 2000 issue had a review article by J. Gibbs titled “Mechanism-based target identification and drug discovery in cancer research.”

Numbered Hypernotes

1. Breast cancer.The NCI's Science behind the News offers a presentation on understanding cancer. The NCI Web site provides a Breast Cancer Home Page with information for patients and health professionals. A breast cancer overview is provided by the In Touch Web site, which also provides a presentation on cancer genetics. OncoLink provides an overview of breast cancer. A presentation on the biology of breast cancer is offered by the Cornell Program on Breast Cancer and Environmental Risk Factors in New York State. Lecture notes on neoplasia by R. Mellors are made available by the Weill Education Center of the Weill Medical College of Cornell University. CATS (Computer Assisted Teaching System) from the University of Vermont College of Medicine provides an introduction to neoplasia and lecture notes on the molecular pathobiology of neoplasia for a general pathology course.

2. Tamoxifen. An entry for tamoxifen is included in the companion Web site for the third edition of Biochemistry by Mathews, van Holde, and Ahern. The Chemistry Information Technology Centre at the University of Oxford featured tamoxifen as a Molecule of the Month. BBC News offers a medical note on tamoxifen. CancerHelp UK provides a chronology of tamoxifen titled “Developing a new drug: The tamoxifen story.” InteliHealth makes available an article titled “Tamoxifen: Its history and future.” The Imaginis Web site, a resource for information about breast cancer and its treatment sponsored by Siemens, provides information about tamoxifen. A student project by H. Tanner on tamoxifen is made available by the Department of Chemistry, Imperial College of Science, Technology and Medicine, London. The NCI's Cancer Information Service provides a fact sheet about tamoxifen. The Mosby's Drug Consult Web site includes an entry for tamoxifen citrate. Tamoxifen information is provided by the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration. The ISI Essential Science Indicators Web site offers an interview with V. C. Jordan about tamoxifen.

3. Cancer chemoprevention.The American Society of Clinical Oncology offers a feature article about chemoprevention. The March 2000 issue of Carcinogenesis had an article by M. Sporn and N. Suh titled “Chemoprevention of cancer.” The June 1999 issue of Endocrine Reviews had an article by V. C. Jordan and M. Morrow titled “Tamoxifen, raloxifene, and the prevention of breast cancer” (2). NCI offers a 14 September 1998 press release about the results of the Breast Cancer Prevention Trial (BCPT). The 16 June 1999 issue of JAMA had an article by S. Cummings et al. titled “The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial” and an editorial by A. Franks and K. Steinberg titled “Encouraging news from the SERM frontier.” The January-February 2001 issue of ISI's Science Watch had an article by D. Sharpe titled “Raloxifene gets two hits from the same clinical trial.” Cancer Prevention: Molecular Mechanisms to Clinical Applications (volume 952, December 2001, of the Annals of the New York Academy of Sciences) includes a contribution by V. C. Jordan titled “Chemoprevention with antiestrogens: The beginning of the end for breast cancer” and a contribution by C. Fabian and B. Kimler titled “Beyond tamoxifen: New endpoints for breast cancer chemoprevention, new drugs for breast cancer prevention.” Selective Estrogen Receptor Modulators (SERMS) has a contribution by M. Dickler and L. Norton titled “The MORE trial: Multiple outcomes for raloxifene evaluation.” NCI offers an information digest about the Study of Tamoxifen and Raloxifene (STAR) trial; a fact sheet is provided. The NSABP (National Surgical Adjuvant Breast and Bowel Study) provides a STAR Web site.

4. Raloxifene. RxList, an Internet drug index, provides information about raloxifene. The FDA's CDER provides information about Evista (raloxifene). The National Women's Health Network offers a fact sheet on raloxifene. The Mosby's Drug Consult Web site includes an entry for raloxifene hydrochloride. Osteoporosis Online offers a presentation on raloxifene titled “SERMs: Their role in the prevention and treatment of osteoporosis.” The October 2000 issue of the Oncologist had a conference paper by D. Muchmore titled “Raloxifene: A selective estrogen receptor modulator (SERM) with multiple target system effects.” The 15 September 1999 issue of the American Family Physician had an article by J. Scott, C. da Camara, and J. E. Early titled “Raloxifene: A selective estrogen receptor modulator.” The 7 August 1999 issue of BMJ had an editorial by V. C. Jordan and M. Morrow titled “Raloxifene as a multifunctional medicine?”

5. Tamoxifen and endometrial cancer. Medem makes available an April 2000 committee opinion report of the American College of Obstetricians and Gynecologists titled “Tamoxifen and endometrial cancer.” The March-April 1996 issue of Cancer Control, the journal of the Moffitt Cancer Center, had an article by R. Barakat titled “Tamoxifen and endometrial cancer.” BBC News offers a 16 February 1999 article titled “Cancer risk from tamoxifen.” The Imaginis Web site provides a 14 September 2000 news article titled “Study finds tamoxifen may significantly increase risk of uterine cancer.”

6. Y. Shang and M. Brown are at the Dana-Farber Cancer Institute, Boston. The Myles Brown Laboratory has a home page.

7. Estrogen receptor. J. Brown, Department of Molecular Biosciences, University of Kansas, provides an introduction to receptors. An introduction to hormone receptors is provided by the Biochemistry companion Web site. U. Desai, Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, offers lecture notes on estrogens for a course on medicinal chemistry. The Estrogen Receptor Resource is part of the Nuclear Receptor Resource Project. The SWISS-PROT protein database has an entry for estrogen receptor. Online Mendelian Inheritance in Man (OMIM) has an entry for estrogen receptor. P. O'Hara, Department of Chemistry, Amherst College, offers illustrated presentations on the estrogen receptor (steroid binding domain) and the estrogen receptor (DNA binding domain) for a biochemistry course. Student projects by M. Georgy on the estrogen receptor ligand binding domain and the estrogen receptor DNA-binding domain are made available by J. Newman, Department of Biology, Lycoming College, Williamsport, PA. The Theoretical Biophysics Group, University of Illinois, offers a presentation on nuclear hormone receptors and a research presentation on estrogen receptor interacting with DNA. The 5 September 1997 issue of Science had a Research News article by E. Pennisi titled “Differing roles found for estrogen's two receptors.”

8. Selective estrogen receptor modulators (SERMs). Selective estrogen-receptor modulator is defined in the On-line Medical Dictionary. The Imaginis Web site provides an introduction to SERMs. Selective Estrogen Receptor Modulators (SERMS) includes a section on the basic biology of SERMs and a section of figures and tables summarizing information about SERMS. The June 2001 issue of Chemistry in Britain had an article by G. Jaouen about research on SERMs titled “Improving the odds.” The November 2000 issue of the Journal of Pharmacology and Experimental Therapeutics had a review article by M. Dutertre and C. Smith titled “Molecular mechanisms of selective estrogen receptor modulator (SERM) action.”

9. Agonist and antagonist are defined in a Dictionary of Biology, available on the xrefer Web site. Agonist and antagonist are defined in the introduction to hormones, receptors and target cells provided by R. Bowen's Pathophysiology of the Endocrine System, a Web textbook. Entries for agonist and antagonist are included in the pharmacology guide provided by the GlaxoWellcome R&D Web site; a presentation on the principles of agonist and antagonist action is also provided. The Agard Lab at the Department of Biochemistry and Biophysics, University of California at San Francisco, offers a research presentation on the molecular mechanisms of agonism and antagonism for the estrogen receptor.

10. Pharmacology of estrogens and estrogen receptors. Kimball's Biology Pages offers an introduction to steroid hormone receptors and their response elements. A presentation titled “The new science of estrogen receptors” is made available by the U.S. Pharmacist Web site. Selective Estrogen Receptor Modulators (SERMS) includes a contribution by D. McDonnell, C.-Y. Chang, and J. Norris titled “Capitalizing on the complexities of estrogen receptor pharmacology in the quest for the perfect SERM,” a contribution by N. McKenna and B. O'Malley titled “Nuclear receptors, coregulators, ligands, and selective receptor modulators: Making sense of the patchwork quilt,” and a contribution by B. Katzenellenbogen et al. titled “Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles.”

11. Structure of the estrogen receptor bound to different ligands. W. McClure's Molecular Models for Biochemistry includes a section on estrogen receptor structures and functions with a collection of estrogen receptor structure models including presentations on the estrogen receptor bound with estradiol, raloxifene, and tamoxifen. The Protein Data Bank has structure explorer entries for the estrogen receptor bound to tamoxifen and raloxifene. The University of Chicago issued a 23 December 1998 press release titled “Tamoxifen in action” about the research of Shiau et al. (9) on receptor structures. G. Greene, Ben May Institute for Cancer Research, University of Chicago, provides a research presentation about this research.

12. Coactivators and corepressors. A report of a workshop on coactivators and corepressors in gene expression is made available by the National Institute of Diabetes and Digestive and Kidney Diseases. M. Bagchi, Center for Reproductive Biology, University of Illinois, provides an introduction to coactivators and corepressors in a discussion of his research interests. The Nuclear Receptor and Coregulator Group, Department of Biosciences, Novum, Karolinska Institutet, Stockholm, offers a research presentation on coregulators. The December 1999 issue of the Journal of Molecular Endocrinology had a review article (the full text is available in Adobe Acrobat format) by T. Collingwood, F. Urnov, and A. Wolffe titled “Nuclear receptors: Coactivators, corepressors and chromatin remodeling in the control of transcription.” The February 2001 issue of Cellular and Molecular Life Sciences had a review article (available in Adobe Acrobat format) by J. W. Lee et al. titled “Transcriptional coregulators of the nuclear receptor superfamily: Coactivators and corepressors.” The 5 October 2001 issue of the Journal of Biological Chemistry had a review article by M. Rosenfeld and C. Glass titled “Coregulator codes of transcriptional regulation by nuclear receptors” (13) and a review article by J. Hall, J. Couse, and K. Korach titled “The multifaceted mechanisms of estradiol and estrogen receptor signaling” (12).

13. Estradiol is defined in the American Heritage Dictionary of the English Language and in the On-line Medical Dictionary. The Biochemistry companion Web site offers entries for estrogen and estradiol in the section on concepts, molecules, and enzymes. RxList has an entry for estradiol with a section on the clinical pharmacology of estrogens. from AstraZeneca provides illustrations of the molecular mechanisms of action of estradiol and tamoxifen. The Indiana University Molecular Structure Center provides an illustration of the structure of estradiol.

14. The steroid receptor coactivator (SRC) family and SRC1.The TrEMBL supplement to SWISS-PROT has an entry for steroid receptor coactivator-1. OMIM has an entry for nuclear receptor coactivator 1; NCOA1 (SRC1). M. Lacroix's SciMedWeb Molecular Breast Cancer Web site provides information on SRC1. J. Xu, Department of Molecular and Cellular Biology, Baylor College of Medicine, offers a research presentation on steroid receptor coactivators. A section on the SRC family of coactivators is included in a chapter by F. DeMayo et al. titled “Mechanisms of action of estrogen and progesterone” that appeared in Endometriosis: Emerging Research and Intervention Strategies (Annals of the New York Academy of Sciences, vol. 955, March 2002).

15. Tamoxifen resistance.The 26 November 1998 issue of the New England Journal of Medicine had a review article by C. K. Osborne titled “Taxmoxifen in the treatment of breast cancer” (17), which includes a discussion of tamoxifen resistance. The 30 July 1999 issue of Science had a report by J. Norris et al. titled “Peptide antagonists of the human estrogen receptor.” The Duke University Medical Center issued a 29 July 1999 press release about this research titled “Duke/Novalon researchers identify potential mechanism behind tamoxifen resistance in breast cancers.” The Imaginis Web site offers a 30 July 2000 news report titled “New research sheds light on why women build resistance to tamoxifen breast cancer therapy.”

16. B. S. Katzenellenbogen is in the Department of Molecular and Integrative Physiology and in the Department of Cell and Structural Biology, University of Illinois.

17. J. A. Katzenellenbogen is in the Department of Chemistry, University of Illinois.


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