The Science of Selective Estrogen Receptor Modulators ... · women. To the casual observer, the...
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The Science of Selective Estrogen Receptor Modulators: Concept to Clinical Practice 55 Commentary on Lippman et al., p. 5242 V. Craig Jordan Lippman et al. (1) assess the effect of raloxifene on the incidence of breast cancer in women with defined risk factors. However, raloxifene is used in clinical practice for the treatment and prevention of osteoporosis in postmenopausal women. To the casual observer, the application of a medicine to treat and prevent osteoporosis would seem to be counter- intuitive as estrogen is known to build bones. It therefore follows that if estrogens build bones in postmenopausal women and estrogens support breast cancer growth (2), then why is there a reported decrease in breast cancer in women taking raloxifene to treat osteoporosis (3, 4)? The reason is that the class of drugs originally known as ‘‘nonsteroidal anties- trogens’’ are in fact selective estrogen receptor (ER) modulators (SERM), which turn on or turn off target sites around a woman’s body. The recognition of targeted estrogenic and antiestrogenic actions for the two principal players tamoxifen and raloxifene was defined in the latter half of the 1980s (Fig. 1; ref. 5). The concept being tested by Lippman et al. (1) is the roadmap described at the end of the 1980s (2, 6) and used by the pharmaceutical industry to develop numerous new SERMs as potential multifunctional medicines (7). The Concept A plan to prevent breast cancer as a public health initiative was initially described at the First International Chemo- prevention meeting in New York in 1987. It is reasonable to simply state the proposal, published from the 1987 meeting and subsequently refined and presented at the annual meeting of the AACR in San Francisco in 1989. ‘‘The majority of breast cancer occurs unexpectedly and from unknown origin. Great efforts are being focused on the identification of a population of high-risk women to test ‘chemopreventive’ agents. But, are resources being used less than optimally? An alternative would be to seize on the developing clues provided by an extensive clinical investigation of available antiestrogens. Could analogues be developed to treat osteoporosis or even retard the development of athero- sclerosis? If this proved to be true, then a majority of women in general would be treated for these conditions as soon as menopause occurred. Should the agent also retain antibreast tumor actions, then it might be expected to act as a chemo- suppressive on all developing breast cancers if these have an evolution from hormone-dependent disease to hormone- independent disease. A bold commitment to drug discovery and clinical pharmacology will potentially place us in a key position to prevent the development of breast cancer by the end of this century (6).’’ The concept was refined by 1990 (2). ‘‘We have obtained valuable clinical information about this group of drugs that can be applied in other disease states. Research does not travel in 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 apparently, 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.’’ This concept is exactly what has been translated to clinical practice (3, 4): use a SERM (raloxifene) to treat osteoporosis and reduce the incidence of breast cancer as a beneficial side effect. Laboratory Evidence for SERM Action During the 1980s, tamoxifen became the first antiestrogenic therapy targeted to the ER for adjuvant therapy (8). The principle was simple. Those patients with ER-positive breast cancer were most likely to have estrogen-stimulated tumors and tamoxifen could be used to block estrogen action. Current analysis of worldwide clinical trials shows that tamoxifen increases not only disease-free survival but also overall survival (9). In the 1980s, few side effects were noted with tamoxifen compared with cytotoxic chemotherapy so the antiestrogen tamoxifen became the standard of care for ER-positive breast cancer whether the patients were node positive or node negative. The widespread use of tamoxifen in node-negative (low risk) breast cancer patients increased interest in testing the worth of tamoxifen as a potential chemopreventive in high-risk women. The reasons were simple: tamoxifen, an antiestrogen, prevented mammary carcinogenesis in animals (10), reduced the occurrence of contralateral breast cancer (9), and at that time, had no major side effects. Unfortunately, the received wisdom in the 1980s was that estrogen was essential to build bones and prevent osteoporosis. In addition, estrogen lowers circulating choles- terol so there was every reason to believe at that time that The Biology Behind Author’s Affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania Received 5/10/06; accepted 5/18/06. Grant support: Specialized Programs of Research Excellence in Breast Cancer grants CA89018 and R01 GM061756, Avon Foundation, and Fox Chase Cancer Center Weg Fund (V. Craig Jordan). Requests for reprints: V. Craig Jordan, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497. Phone: 215-728-7410; Fax: 215-728-7034; E-mail: v.craig.jordan@fccc.edu. F 2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-1136 www.aacrjournals.org Clin Cancer Res 2006;12(17) September 1, 2006 5010 Cancer Research. on October 17, 2020. © 2006 American Association for clincancerres.aacrjournals.org Downloaded from
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The Science of Selective Estrogen Receptor Modulators:Concept to Clinical Practice55 Commentary on Lippman et al., p. 5242
V. CraigJordan
Lippman et al. (1) assess the effect of raloxifene on theincidence of breast cancer in women with defined risk factors.However, raloxifene is used in clinical practice for thetreatment and prevention of osteoporosis in postmenopausalwomen. To the casual observer, the application of a medicineto treat and prevent osteoporosis would seem to be counter-intuitive as estrogen is known to build bones. It thereforefollows that if estrogens build bones in postmenopausalwomen and estrogens support breast cancer growth (2), thenwhy is there a reported decrease in breast cancer in womentaking raloxifene to treat osteoporosis (3, 4)? The reason is thatthe class of drugs originally known as ‘‘nonsteroidal anties-trogens’’ are in fact selective estrogen receptor (ER) modulators(SERM), which turn on or turn off target sites around awoman’s body. The recognition of targeted estrogenic andantiestrogenic actions for the two principal players tamoxifenand raloxifene was defined in the latter half of the 1980s(Fig. 1; ref. 5). The concept being tested by Lippman et al. (1) isthe roadmap described at the end of the 1980s (2, 6) and usedby the pharmaceutical industry to develop numerous newSERMs as potential multifunctional medicines (7).
The Concept
A plan to prevent breast cancer as a public health initiativewas initially described at the First International Chemo-prevention meeting in New York in 1987. It is reasonable tosimply state the proposal, published from the 1987 meetingand subsequently refined and presented at the annual meetingof the AACR in San Francisco in 1989.‘‘The majority of breast cancer occurs unexpectedly and from
unknown origin. Great efforts are being focused on theidentification of a population of high-risk women to test‘chemopreventive’ agents. But, are resources being used lessthan optimally? An alternative would be to seize on thedeveloping clues provided by an extensive clinical investigationof available antiestrogens. Could analogues be developed totreat osteoporosis or even retard the development of athero-sclerosis? If this proved to be true, then a majority of women in
general would be treated for these conditions as soon asmenopause occurred. Should the agent also retain antibreasttumor actions, then it might be expected to act as a chemo-suppressive on all developing breast cancers if these have anevolution from hormone-dependent disease to hormone-independent disease. A bold commitment to drug discoveryand clinical pharmacology will potentially place us in a keyposition to prevent the development of breast cancer by the endof this century (6).’’ The concept was refined by 1990 (2). ‘‘Wehave obtained valuable clinical information about this group ofdrugs that can be applied in other disease states. Research doesnot travel in straight lines and observations in one field ofscience often become major discoveries in another. Importantclues have been garnered about the effects of tamoxifen on boneand lipids, so apparently, derivatives could find targetedapplications to retard osteoporosis or atherosclerosis. Theubiquitous application of novel compounds to prevent diseasesassociated with the progressive changes after menopause may,as a side effect, significantly retard the development of breastcancer. The target population would be postmenopausalwomen in general, thereby avoiding the requirement to selecta high-risk group to prevent breast cancer.’’ This concept isexactly what has been translated to clinical practice (3, 4):use a SERM (raloxifene) to treat osteoporosis and reducethe incidence of breast cancer as a beneficial side effect.
Laboratory Evidence for SERMAction
During the 1980s, tamoxifen became the first antiestrogenictherapy targeted to the ER for adjuvant therapy (8). Theprinciple was simple. Those patients with ER-positive breastcancer were most likely to have estrogen-stimulated tumorsand tamoxifen could be used to block estrogen action. Currentanalysis of worldwide clinical trials shows that tamoxifenincreases not only disease-free survival but also overallsurvival (9). In the 1980s, few side effects were noted withtamoxifen compared with cytotoxic chemotherapy so theantiestrogen tamoxifen became the standard of care forER-positive breast cancer whether the patients were nodepositive or node negative. The widespread use of tamoxifen innode-negative (low risk) breast cancer patients increasedinterest in testing the worth of tamoxifen as a potentialchemopreventive in high-risk women. The reasons weresimple: tamoxifen, an antiestrogen, prevented mammarycarcinogenesis in animals (10), reduced the occurrence ofcontralateral breast cancer (9), and at that time, had no majorside effects. Unfortunately, the received wisdom in the 1980swas that estrogen was essential to build bones and preventosteoporosis. In addition, estrogen lowers circulating choles-terol so there was every reason to believe at that time that
The Biology Behind
Author’s Affiliation: Fox Chase Cancer Center, Philadelphia, PennsylvaniaReceived 5/10/06; accepted 5/18/06.Grant support: Specialized Programs of Research Excellence in Breast Cancergrants CA89018 and R01GM061756, Avon Foundation, and Fox Chase CancerCenter Weg Fund (V. CraigJordan).Requests for reprints:V. Craig Jordan, Fox Chase Cancer Center, 333 CottmanAvenue, Philadelphia, PA 19111-2497. Phone: 215-728-7410; Fax: 215-728-7034;E-mail: [email protected].
F2006 American Association for Cancer Research.doi:10.1158/1078-0432.CCR-06-1136
www.aacrjournals.orgClin Cancer Res 2006;12(17) September1, 2006 5010
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there would be reductions in coronary heart disease withestrogen replacement. If tamoxifen was used in well womenonly at risk for breast cancer, then there might be a significantdecrease in breast cancer but unacceptable increases inosteoporosis and coronary heart disease. However, progressin translational research was to establish the targetedestrogenic and antiestrogenic actions of the first SERMs (11).Unexpectedly, both tamoxifen and raloxifene (a failed
breast cancer drug known as keoxifene) both maintainedbone density in ovariectomized rats (12) at doses that wouldprevent the development of carcinogen-induced rat mammarytumors (13). These data (i.e., the maintenance of bone densityand the prevention of breast cancer) were translated to theclinic first with tamoxifen (14) and subsequently withraloxifene (3). A difference in the target site–specific actionsof tamoxifen in the mouse uterus or human breast tumortransplanted into immunodeficient mice (15) resulted in the
observation that tamoxifen enhanced the growth of humanER-positive endometrial carcinomas but blocked the growth ofbreast tumors transplanted into the same immunodeficientanimal (16). Again, these data translated to the clinic with areported small but significant increase in the incidence ofendometrial cancer in postmenopausal women (14). Thus,the ER complex was being interpreted differently as separatetarget sites to either stimulate or block growth (15, 16).More importantly, keoxifene (raloxifene) was noted to haveless estrogenic-like actions in the rodent uterus (17) andhuman endometrial cancer (18) and again this translated tothe clinic (3).
Thus, at the end of the 1980s, the foundation for SERMaction had been established with a path for progress inprevention described clearly. The SERM ER complex wasswitching on or switching off target sites around a woman’sbody (Fig. 1).
Fig. 1. The action of the SERMs tamoxifenand raloxifene at target sites around apostmenopausal woman’s body.The SERMsswitch on (estrogenic action) or switchoff (antiestrogenic action) different targetsites.
The Science of SERM
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ModulatingMolecular Mechanisms
During the past decade, there has been an enhancedunderstanding of the complex decision network in tumorsand estrogen target tissues that modulate the actions of theSERM receptor complex (Fig. 2). Although there was originallybelieved to be only one ER, it is now clear that at least two ERs(ER-a and ER-h; ref. 19) can modify estrogen or SERM action.A SERM can choose an ER based on receptor affinity andpharmacokinetics. The two receptors are distributed differentlyaround the human body and may modify ligand interactionsby homodimerization or heterodimerization as well aspossible interaction with other proteins to modulate signaltransduction. Indeed, the idea that the ER is a genomicsignaling mechanism must now be modified because ERs arepresent at the cell membrane to be part of the rapidphosphorylation signal transduction mechanism and are partof the mitochondrial mechanisms for cell survival (20).However, the ligand structure is also important to causedistinct ER folding that will in turn affect the subsequentinteractions with other proteins, such as coactivators orcorepressors. Raloxifene and tamoxifen are a case in pointwith minor differences in ligand interaction with specificamino acids producing different intrinsic estrogen actions (5).The tamoxifen ER complex is more estrogen-like in vitro andthis may extrapolate to more estrogen-like action in uterus. Incontrast, the raloxifene ER complex is much less estrogen-likeand has fewer estrogen-like properties in uterus.The SERM ER complex is modified subsequently by interac-
tion with coactivators that can enhance gene transcription andcorepressors that can reduce gene expression (21). Thephosphorylation cascade from cell surface growth factorreceptors can also enhance ER action further at specificphosphorylation sites on the activating functions of ER (22)or indeed by the phosphorylation of coactivator molecules (23).The interaction of a specific SERM with ER can also
determine whether the SERM ER complex will accumulate orbe degraded through the proteosome system at a specific tissuesite (24). Clearly, accumulation of SERM ER complexes at atarget site creates unanticipated opportunities for the SERMER complex to activate genes through traditional (genomic)or tethered (nongenomic) activation (activator protein sites) ofpromoter regions of a specific genome (Fig. 2).Overall, the coordination of the decision network within the
separate cell types of a target tissue will result in switching on orswitching off tissues around a patient’s body.
AFuture for Pharmacology
Raloxifene seems to offer distinct advantages as a SERM forpostmenopausal women’s health. The fashion of using indef-inite hormone replacement therapy (synthetic estrogen andprogestin) is now past in the wake of the Women’s HealthInitiative (25). In contrast to hormone replacement therapy,raloxifene clearly does not increase the incidence of breastcancer when used long-term to treat osteoporosis. Women havea 65% to 70% decrease in breast cancer incidence (3, 4) andthis is superior to the 50% noted with tamoxifen in theprevention trials (14). But, will raloxifene do as well in thegeneral population of women at risk for breast cancer ratherthan those who already have low estrogen levels and a very low
risk for breast cancer (1)? Tamoxifen and raloxifene arecompetitive inhibitors of estrogen binding to the ER. To actas an antiestrogen in aberrant breast epithelium, the receptormust be blocked all the time. It is known that raloxifene haspoor bioavailability (2%) in women (26) and the group ofSERMs related to raloxifene have very rapid excretion. Incontrast, tamoxifen has an extremely long half-life with druglevels that can be measured up to 6 weeks after stoppingtreatment. Tamoxifen is metabolized to high-affinity antiestro-gens (27), whereas raloxifene is not. It may be that compliancebecomes an issue in healthy postmenopausal women with ahigh body mass index and, as a consequence, higher circulatinglevels of estrogen. The appropriate dose of raloxifene that isgood for building bones may not be optimal for completelyblocking the growth of occult breast cancer over the first 5 yearsof treatment. Only the continuous blockade of occult tumorER may be optimally effective at reducing both invasive andnoninvasive breast cancer when the drug is applied outside thesetting of the Lippman study (1). Analysis of the results of the
Fig. 2. The decision network that a SERMmust navigate to switch on or switchoff an estrogenic response at a target site.1, a SERM has the opportunity to interacteither with membrane-bound ER as part of the cell surface receptor signaltransduction phosphorylation cascade or with the nuclear ERs.The shape of theSERM is important to create optimal antiestrogenic folding of the ER complex. 2,there are two ERs (ER-a and ER-h) that can produce opposing biological actionsbased on the shape (3) or the phosphorylation (4) state of the SERMER complex.There will be an interaction with either a coactivator protein to induce a responseor a corepressor protein to block a response (3). Additionally, based on shape,there may be destruction (5) of the SERMER complex by the proteosomes oraccumulation. Finally, the SERMER complex may activate (6) the promoter regionof genes directly at the DNA (genomic) or via activator protein (AP-1) sites witha protein protein interaction (tethered).
The Biology Behind
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Study of Tamoxifen And Raloxifene (STAR) will be importantfor future studies. Clearly, the next generation of SERMs mayneed to be long acting if they are to become optimal multi-functional agents to prevent breast cancer and osteoporosis.There is value in deciphering the target site–specific actions
of ligands at ER-a and ER-h (28). Numerous diseases may betreated with receptor-specific ligands. However, because the
promise of SERMs has become a clinical reality, this hascaused a re-examination of other members of the steroidreceptor superfamily. In the decades to come, perhapsthere will be selective androgen receptor modulators, selec-tive glucocorticoid receptor modulators, etc. that createa new dimension for multifunctional medicines in medicalpractice.
The Science of SERM
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2006;12:5010-5013. Clin Cancer Res V. Craig Jordan Concept to Clinical PracticeThe Science of Selective Estrogen Receptor Modulators:
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