Selective Estrogen Response Modulators Research Articles

Non-hormonal Chemoprevention

Potential strategies for prevention of breast cancer include lifestyle modification, preventive therapies (i.e., chemoprevention), and surgical prevention. Several therapies (such as selective estrogen response modifiers and aromatase inhibitors) have been shown to prevent breast cancer. However, tolerability and toxicity limit use and these therapies only prevent estrogen receptor–positive (ER) disease. There is emerging data regarding prevention properties of several non-hormonal agents. These agents generally have lower toxicities and seem to be effective for reduction of both ER+ and ER− disease and are often approved for use in other diseases. The purpose of this review is to discuss the data supporting the potential role of these non-hormonal agents for breast cancer prevention. Several studies have demonstrated the potential of aspirin, vitamin D, metformin, and bisphosphonates to prevent breast cancer. The outlined studies support biological mechanisms and show epidemiologic associations but randomized controlled trials are necessary before any of these agents can be recommended for breast cancer prevention. Given the wide spread use of these agents, significant consideration to trial design is needed (i.e., focus on high-risk populations and use of biomarker endpoints). Another important consideration may be the investigation of combinations of agents as suggested by others.

Modern concept of Benign Breast Disorders and its Endocrinological Background

Mastalgia and generalised breast nodularity where a discrete lump cannot be felt called Aberration of Normal Development and Involution (ANDI) is the most common condition leading to breast related consultations. The author's work on this clinical syndrome over the last 3 decades has led to documentation of its natural history, epidemiological study of ANDI, development of objective scales for clinical assessment of breast pain and nodularity, its endocrinological aetiopathogenesis, response prediction of treatment in cyclical mastalgia, a randomized controlled trial of an indigenous selective estrogen response modulator - ormeloxifene and finally a meta-analysis of treatment for this condition. This turned a full wheel bridging gaps in the knowledge of this disorder and led us to evolve an effective, inexpensive treatment of mastalgia with least side effect. The work is dedicated to Professors LE Hughes, Robert E Mansel and Anurag Srivastava.

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention.

Abstract 2167: Infertility and risk of incident endometrial carcinoma: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium

Abstract Background: Nulliparity is an established endometrial cancer risk factor, but whether this association is related to infertility is unclear. Although there are many underlying causes of infertility, few studies have assessed risk relationships according to specific causes. Despite concerns that most treatments induce ovulation and that the endometrium is highly hormonally-responsive, previous studies have provided conflicting results on treatment associations. Methods: To address these issues, we conducted a pooled analysis of 8,151 cases and12,471 controls from 2 cohort and 12 case-control studies conducted in 1982 to 2009 (N. America, Europe, Australia, Asia). All studies provided self-reported infertility, causes and treatments, except for 1 study that relied on data from national registries. Study-specific exposures and covariate data were harmonized across studies. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for study, age, interview year, race, parity, oral contraceptive and menopausal hormone use, and body mass index. If data were not reported for a particular variable, that study was excluded from the variable-specific analysis. Results: Nulliparous women had an elevated endometrial cancer risk compared with parous women (adjusted OR=1.73; 95% CI: 1.58-1.90).Women with self-reported infertility also had an increased risk (adjusted OR=1.22; 95% CI: 1.13-1.32) compared with those without infertility issues, even after adjusting for parity; the strongest associations was seen among studies that defined infertility as unsuccessfully trying to conceive for 2+ years (adjusted OR=1.31; 95% CI: 1.07-1.60). Infertility was associated with similar risks among nulliparous (1.22; 1.10-1.48) and parous (1.22; 1.12-1.34) women, although there was no increased risk associated with infertility among those who had given birth to 3+ children. Two infertility causes associated with risk elevation were endometriosis (adjusted OR=2.08; 95% CI: 1.46-2.95 compared with women no infertility problems) and anovulation (adjusted OR=1.40; 95% CI: 1.16-1.70). Based on relatively small numbers, none of the individual treatments (in vitro fertilization, selective estrogen response modulators, gonatropins, progestins, estrogens) were substantially related to risk. Conclusion: Based on mainly self-reported infertility data, we found that parity and infertility independently contribute to endometrial cancer risk, with parity seemingly being the predominant risk predictor. Understanding residual endometrial cancer relationships related to causes of infertility and infertility treatment may benefit from documented medical information on causes of infertility and treatment parameters. Citation Format: Hannah P. Yang, Linda S. Cook, Elisabete Weiderpass, Hans-Olov Adami, Kristin E. Anderson, Hui Cai, James R. Cerhan, Tess Clendenen, Ashley S. Felix, Christine Friedenreich, Montserrat Garcia-Closas, Marc T. Goodman, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Susan E. McCann, Kristen B. Moysich, Sara H. Olson, Malcolm C. Pike, Silvia Polidoro, Fulvio Ricceri, Harvey Risch, Carlotta Sacerdote, V. Wendy Setiawan, Xiao Ou Shu, Amanda B. Spurdle, Britton Trabert, Penelope M. Webb, Nicolas Wentzensen, Yong-Bing Xiang, Youming Xu, Herbert Yu, Anne Zeleniuch-Jacquotte, Louise A. Brinton. Infertility and risk of incident endometrial carcinoma: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2167. doi:10.1158/1538-7445.AM2014-2167

Role of hormones in cancer prevention.

Risk for breast cancer can be easily and rapidly assessed using validated, quantitative models. Multiple randomized studies show that the selective estrogen response modifiers (SERMs) tamoxifen and raloxifene can safely reduce the risk of invasive breast cancer in both pre- and postmenopausal women. Treatment resulted in a 38% reduction in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. Reduction was larger in the first 5 years of follow-up than in years 5 to 10, but no studies treated patients for longer than 5 years. Thromboembolic events were significantly increased with all SERMs, whereas vertebral fractures were reduced. Tamoxifen provides net benefit to all premenopausal women who are at increased risk, whereas raloxifene reduces risk nearly as much in postmenopausal women and offers increased safety. Both tamoxifen and raloxifene reduce the incidence of in situ cancers. Lasofoxifene reduced the risk of breast cancer by 79% in postmenopausal women with osteoporosis. The MAP3 trial showed a 65% reduction in the annual incidence of invasive breast cancer in postmenopausal women who were at moderately increased risk for breast cancer who took the aromatase inhibitor exemestane. The IBIS-II trial showed a 53% reduction in the risk of invasive breast cancer in postmenopausal women aged 40 to 70 who took the aromatase inhibitor anastrozole. Of the 50 million white women in the United States aged 35 to 79, 2.4 million would have a positive benefit/risk index for chemoprevention.

Innate Immunity in the Vagina (Part I): Estradiol Inhibits HBD2 and Elafin Secretion by Human Vaginal Epithelial Cells

Vaginal epithelial cells (VEC) are the first line of defense against incoming pathogens in the female reproductive tract. Their ability to produce the anti-HIV molecules elafin and HBD2 under hormonal stimulation is unknown. Vaginal epithelial cells were recovered using a menstrual cup and cultured overnight prior to treatment with estradiol (E₂), progesterone (P₄) or a panel of selective estrogen response modulators (SERMs). Conditioned media were recovered and analyzed for protein concentration and anti-HIV activity. E₂ significantly decreased the secretion of HBD2 and elafin by VEC over 48 hrs, while P4 and the SERMs (tamoxifen, PHTTP, ICI or Y134) had no effect. VEC conditioned media from E₂ -treated cells had no anti-HIV activity, while that from E₂ /P₄ -treated cells significantly inhibited HIV-BaL infection. The menstrual cup allows for effective recovery of primary VEC. Their production of HBD2 and elafin is sensitive to E₂, suggesting that innate immune protection varies in the vagina across the menstrual cycle.

What are the physiological estrogens?

Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ4 bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ5-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these “alternative” estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities.

Abstract A58: High Throughput Search for a Combination Cancer Preventive Treatment

Abstract Identification of safer chemopreventive drugs is essential for the future of cancer preventive treatment. Although the feasibility for chemoprevention of estrogen receptor (ER) -positive breast cancers has been exemplified by the use of selective estrogen response modifiers (SERMs), we are still lacking preventive options for many other disease types, including breast cancers not dependent on ER status. Rexinoids are a class of agents that effectively reduce the incidence of both ER-positive and -negative tumors in animal models of breast cancer and thus may be better cancer preventive drugs than the current standard SERMs. However, significant side-effects at the effective clinical dose, including hypertriglyceridemia and weight gain, limit its generalized use. A phase II biomarker trial of the synthetic rexinoid, bexarotene (Targretin, LGD1069) demonstrated that bexarotene reduces expression of the proliferation markers Ki67 and Cyclin D1 in normal breast epithelium of postmenopausal women, suggesting that the cancer preventive effects of bexarotene are associated with its ability to elicit cell cycle blockade and inhibit proliferation of premalignant mammary epithelial cells. Here we hypothesize that the combination of repurposed drugs and some small molecule compounds with low dose rexinoid will minimize toxicity and result in effective anti-proliferative in premalignant cells. Therefore, we designed an image-based in vitro assay system to conduct high throughput screens to identify existing drugs and drug-like small molecules which enhance the growth suppressive effect of cancer preventive rexinoids. We used an automated 96 well platform to test the NIH clinical collection of drugs and a library of structurally diverse compounds (MayBridge Hitfinder) alone or in combination with 100nM bexarotene. Through multiparametric determination of cell counts, DNA content and cellular toxicity, we identified combination treatments of premalignant breast cells that fit the above criteria and report on dose-response studies and secondary screens for optimal dose and cell health. Validation of some of the candidate agents and plans for in vivo testing of their chemopreventive activity will be discussed. Citation Format: Ivan P. Uray, Powel H. Brown. High-throughput search for a combination cancer preventive treatment. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A58.

Abstract 4727: Breast cancer prevention and selective estrogen response modulators (SERMs): Pharmacogenomics and differential estrogen and SERM regulation of BRCA1 and BRCA2 expression

Abstract Introduction: The NSABP P-1 and P-2 breast cancer prevention trials have demonstrated that the SERMs tamoxifen and raloxifene can reduce the risk of breast cancer in high risk women. Methods: We performed a nested matched case-control GWAS utilizing DNA from participants enrolled in P-1 and P-2. 592 participants developed invasive breast cancer or ductal carcinoma in situ, and were matched with 1171 controls who did not. Genome-wide genotyping with the Illumina 610-Quad chip and CYP2D6 genotyping for pertinent alleles were performed. Functional genomic studies involved the use of cultured cells, with siRNA knockdown, followed by qRT-PCR and Western blot analyses. Results: Eleven SNPs with p-values < 3E-05 were identified. Twenty one additional SNPs with p < 4E-05 were identified by imputation around the genotyped SNPs on chromosomes (Chrs) 4, 8, 9, 13, 16 and 22, which were then genotyped with the Invader platform. Initial functional genomic studies focused on 6 SNPs on Chr16 (p-values 1.81-9.55E-06), all of which were in ZNF423, a gene encoding a putative zinc-finger protein. The Chr16 minor variant SNP sequences had less risk than the common variant (OR=0.7). Our functional studies showed that incubation of Hs578T cells stably transfected with estrogen receptor (ER) α with 0.1 nM estradiol (E2) induced expression of ZNF423, BRCA1/2 for WT but not variant SNP sequences. There was also a striking difference between E2-induced ZNF423, BRCA1/2 expression for variant and WT SNPs in lymphoblastoid cell lines (LCLs) stably transfected with ERα, with only WT showing induction. ChIP assay showed that ZNF423 could bind to the 5’-flanking region of BRCA1, and reporter gene assays showed that ZNF423 could regulate BRCA1/2 transcription. In LCLs stably transfected with ERα and genotyped for ZNF423 SNPs, estrogen-dependent expression of all 3 genes occurred only in the presence of the WT, but not variant ZNF423 SNP sequences. Blockade of ERα with 4-OH tamoxifen prevented induction of expression in cells with WT sequences, but resulted in gene dose-dependent increases in BRCA1/2 expression in cells with variant SNP sequences-suggested that the minor variant has a “protective” effect during clinical SERM therapy and verified by ChIP assays. Conclusions: The SNPs in ZNF423 identified during GWAS were associated with differential E2-dependent induction of ZNF423, BRCA1 and BRCA2-implying that ZNF423 is “upstream” for the estrogen-dependent induction of BRCA1/2 expression. However, LCLs with variant SNP sequences showed greatly enhanced expression of ZNF423, BRCA1/2 during 4-OH tamoxifen exposure, while cells with WT sequences did not. These results may reveal a novel mechanism for SERM-dependent regulation of BRCA1/2 expression and may have implications for patient selection for SERM therapy. Funded by U10-CA37377, U10-CA69974 and U14-GM61388. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4727. doi:10.1158/1538-7445.AM2011-4727

New Approaches to Making the Microenvironment of the Female Reproductive Tract Hostile to HIV

The studies presented in this review explore three distinct areas with potential for inhibiting HIV infection in women. Based on emerging information from the physiology, endocrinology and immunology of the female reproductive tract (FRT), we propose unique 'works in progress' for protecting women from HIV. Various aspects of FRT immunity are suppressed by estradiol during the menstrual cycle, making women more susceptible to HIV infection. By engineering commensal Lactobacillus to secrete the anti-HIV molecule Elafin as estradiol levels increase, women could be protected from HIV infection. Selective estrogen response modifiers enhance barrier integrity and enhance secretion of protective anti-HIV molecules. Finally, understanding the interactions and regulation of FRT endogenous antimicrobials, proteases, antiproteases, etc., all of which are under hormonal control, will open new avenues to therapeutic manipulation of the FRT mucosal microenvironment. By seeking new alternatives to preventing HIV infection in women, we may finally disrupt the HIV pandemic.

Abstract P6-15-06: Heat Shock Protein 90 Inhibition Limits the Emergence of Tamoxifen Resistance

Abstract Background: A major limitation to the efficacy of hormonal therapies in the management of advanced breast cancers is the frequent development of acquired resistance. The mechanisms underlying such resistance are complex, but likely involve alterations in Estrogen Receptor (ER)-cofactor associations at Estrogen Responsive Elements (EREs) on the DNA and/or enhanced ER phosphorylation through growth factor signaling pathways. Indeed, altered cofactor association in some breast cancers may eventually lead to stimulation of growth by Selective Estrogen Response Modifiers (SERMs) such as tamoxifen (Tam). Because resistance poses such a prominent problem in the use of SERMs, we have examined inhibition of the molecular chaperone heat shock protein 90 (Hsp90) as an alternative approach to targeting ER function, one that could be used in combination with Tam to prevent resistance and provide more durable disease control. Materials and Methods: Using MCF-7 breast cancer cells, disruption of ER function by ansamycin-based Hsp90 inhibitors (geldanamycin, 17AAG) and a highly potent and well-tolerated next-generation Hsp90 inhibitor (STA-9090) was monitored in the presence and absence of Tam. ER protein levels, localization, transcriptional activating activity and DNA binding were measured using standard techniques. Small molecules and lentiviral-mediated RNAi knockdown were used to determine the impact of Hsp90 compromise on the emergence of Tam-resistant clones in colony-forming assays. Results: In the absence of Tam, Hsp90 inhibitors markedly deplete cellular ER levels by stimulating its proteasome-mediated degradation. Depletion is inhibited in cells exposed to Tam and the related antagonist, raloxifene, but not the pure antiestrogen fulvestrant. In detergent-soluble fractions, Hsp90 inhibition induces expected alterations in composition of multi-protein ER-chaperone complexes despite the presence of Tam. Using chromatin immunoprecipitation, however, we found that Tam causes prolonged association of ER with the DNA in stalled transcriptional complexes, thereby retaining the protein in the nucleus and diminishing its destabilization by Hsp90 inhibitors. Nevertheless, Hsp90 inhibition still appears to enhance the activity of Tam in cell culture, probably by depleting a pool of residual ER that is not tightly associated with promoter elements in the presence of Tam. The net effect of combining Tam with Hsp90 inhibition, whether achieved by genetic knockdown or by concentrations of Hsp90 inhibitor that have no overt anticancer activity alone, is to dramatically limit the emergence of Tam resistant clones in cell culture. Experiments in estrogen-supplemented mice bearing MCF-7 xenografts are underway to see whether a similar effect can be achieved in vivo. Discussion: Hsp90 inhibition decreases the survival of hormone-dependent breast cancer cells and prevents the emergence of hormone resistance in cell culture. If confirmed by ongoing animal studies, these findings provide a strong pre-clinical rationale for evaluating combined Tamoxifen-Hsp90 inhibitor treatment in patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-06.

Prevention Strategies in Prostate Cancer

Prostate cancer (PCa) prevention has been an exciting and controversial topic since the results of the Prostate Cancer Prevention Trial (PCPT) were published. With the recently published results of the reduce (Reduction by Dutasteride of Prostate Cancer Events) trial, interest in this topic is at a peak. Primary pca prevention will be unlikely to affect mortality significantly, but the reduction in overtreatment and the effect on quality of life from the avoidance of a cancer diagnosis are important factors to consider.This review provides a comparative update on the REDUCE and PCPT trials and some clinical recommendations. Other potential primary preventive strategies with statins, selective estrogen response modulators, and nutraceutical compounds-including current evidence for these agents and their roles in clinical practice-are discussed. Many substances that have been examined in the primary prevention of pca and for which clinical data are either negative or particularly weak are not covered.The future of PCa prevention continues to expand, with several ongoing clinical trials and much interest in tertiary prostate cancer prevention.

Suicidal Risk in a Patient Receiving Tamoxifen Treatment for Breast Cancer

To the Editor: Tamoxifen is a first-generation selective estrogen response modulator widely used in breast cancer. We have found no reported case of suicide linked to tamoxifen. We report a case of a 53-year-old woman who made a dramatic suicide attempt following a breast cancer treatment with tamoxifen. Case report. Ms A, a 53-year-old mother of 3 children with no psychiatric antecedents, was diagnosed in November 2006 with estrogen receptor–positive breast cancer. She quickly underwent a partial mastectomy followed by radiotherapy. She was not particularly worried following the discovery of her cancer, as it had been discovered at an early stage. Tamoxifen was started in February 2007. After tamoxifen treatment was begun, she progressively developed insomnia, hot flushes, unusual sweating, urinary infections, buzzing in the ears, memory and concentration problems, and an overwhelming fatigue. She also lost her appetite and was unable to taste salt as before. She lost 10 kg in 6 months. Several of these symptoms are typical of estrogen suppression therapy. Her fatigue, loss of appetite, and depressive mood seemed to justify the introduction of antidepressants: venlafaxine was started at 75 mg/d and continued for 15 days but was stopped due to a worsening of excessive sweating. It was followed by escitalopram at 10 mg/d titrated to 20 mg/d after 15 days. In July 2007, she experienced hemorrhoidal thrombosis and vaginal discharge, side effects also commonly seen with estrogen suppression therapy. At that time, tamoxifen was stopped. In August, escitalopram, which was given for 2 months without results, was replaced by mirtazapine at 30 mg/d by her general practitioner. She was then feeling hopeless and exhausted, and she considered herself to be such a burden on her husband and children that she shot herself in the belly with her husband's shotgun 2 days after this change of treatment. She survived but had to undergo right nephrectomy and gall bladder exeresis. Her mood gradually improved, and she regained weight rapidly despite her life-rescuing intervention. She decided to stop mirtazapine by herself after 2 months of treatment. Her condition continued to improve: the overwhelming fatigue totally subsided, her taste for food returned completely, and her memory and concentration returned to normal levels. However, she abruptly relapsed in March 2008, showing marked psychomotor retardation and concentration problems. Bupropion 150 mg/d and mirtazapine 30 mg/d were introduced; no improvement was seen after 1 month. As her family, and her general practitioner, reported that her mood and energy level were somewhat above normal after her first depressive episode, and in fact reflected her usual self, the possibility of a mood disorder belonging to the spectrum of bipolar disorder type II1 was evoked and lamotrigine was introduced. Her mood totally returned to its usual state after 2 months. Bupropion and mirtazapine were both stopped by the patient another 2 months afterward. Her mood has remained stable ever since with continual treatment with lamotrigine 200 mg/d. Depression and anxiety are frequent in breast cancer due to psychological adaptation difficulties and to consequences of treatment procedures.2 Depression was seen largely after cancer diagnosis and treatment in our patient. Improvement of her first episode followed tamoxifen suppression. The second episode did not follow any observable cause. Its beginning was abrupt, and it was characterized by psychomotor retardation and contrasted markedly with the usual mood of the patient, which both before and between depressive episodes was characterized by elated mood and unusually high activity and energy level. As no depressive episode was observed before her 53rd year, we suggest that tamoxifen could have precipitated the onset of a mood disorder, which appears to be stabilized with the use of lamotrigine. Reported rates of tamoxifen-induced depression vary from 1% to 17%.3 As noted, we have found no reported case of suicide linked to tamoxifen. The relationship between estrogen and mood is well known. Estradiol increases serotonin receptor density and increases urinary excretion of serotonin metabolite, reflecting an increase in production. Tamoxifen crosses the blood-brain barrier, and its antagonist properties could block the antidepressant effects normally produced by estrogen. Tamoxifen has recently been proposed as a treatment of mania, further suggesting a possible role in mood regulation.4 Suicidal behaviors have been linked to low serotonergic function in women with genetic predisposition.5 Some women could be at risk to show suicidal impulses if treated with estrogen suppression therapy, depending on the constitutional polymorphism of their serotonergic system. Depressive symptoms should be carefully monitored after tamoxifen treatment induction, as some women might be particularly sensitive to estrogen-suppression effects on mood, which could lead to a possible suicidal outcome.

Breast cancer prevention in countries with diverse resources

Breast cancer is the most common invasive cancer in women globally, and it affects more than 1 million women worldwide each year. It is a preventable disease in part, and primary care providers and public health programs play a key role in providing cancer preventive care. There are several health behaviors that may reduce the risk of breast cancer, including prolonged lactation; regular physical activity; avoiding overweight, obesity, and lifetime weight gain; avoiding excess alcohol intake; avoiding prolonged use of exogenous hormone therapy; and avoiding excessive radiation. These behaviors, although they have not been proven in clinical trials to reduce risk, are likely to be beneficial; information on them can be provided as a prevention strategy in countries of diverse means, although the methods of information delivery and follow-up will depend on financial and personnel resources. Many of these health behaviors can reduce the risk for other chronic diseases and, thus, may be of great interest for general public health. In high resource level countries, additional prevention methods are available for high-risk women, including selective estrogen response modulators and, for women at very high risk, bilateral prophylactic mastectomy and bilateral oophorectomy. Most women can benefit from advice and preventive care for reducing their risk for breast cancer.

Chemopreventive effects of celecoxib are limited to hormonally responsive mammary carcinomas in the neu-induced retroviral rat model

IntroductionWhile current breast cancer chemoprevention strategies using selective estrogen response modulators and aromatase inhibitors are quite successful, their effects are limited to hormonally responsive breast cancer. Hormonally nonresponsive breast cancer (including estrogen receptor-negative cancer) is associated with poor prognosis for patients, and few chemoprevention agents exist for this type of cancer. The cyclooxygenase-2 inhibitor celecoxib (Celebrex®) is a nonsteroidal anti-inflammatory drug and as such is a potential candidate for the prevention of hormonally nonresponsive breast cancer.MethodsThe chemopreventive effects of celecoxib were evaluated in the neu-induced retroviral rat mammary carcinogenesis model, to assess the efficacy of celecoxib on hormonally responsive and hormonally nonresponsive mammary carcinomas.ResultsDietary celecoxib at 1,200 mg/kg diet was highly efficacious in the prevention of hormonally responsive mammary carcinomas in intact rats, decreasing tumor multiplicity by 56% (P < 0.0001) and by 74% (P = 0.0002) in two independent experiments. No significant effect was found, however, on hormonally nonresponsive mammary carcinomas of ovariectomized rats. Treatment with a combination diet, consisting of tamoxifen at 2 mg/kg diet and celecoxib at 1,200 mg/kg diet, reduced tumor multiplicity by 72% (P = 0.0002) in intact rats. This reduction was not statistically different from that observed with celecoxib alone. Furthermore, long-term treatment with celecoxib was not associated with reductions in tumor volume in either intact rats or ovariectomized rats. In contrast, tamoxifen treatment and the combination regimen caused significant reductions in tumor volumes in intact rats (P = 0.01 and P = 0.004, respectively). Consistent with these data, decreases in proliferation and increases in apoptosis were detected in tamoxifen-treated and combination diet-treated tumors. No such modulations were observed in celecoxib-treated tumors.ConclusionThe chemopreventive effects of celecoxib appear to be limited to modulations in multiplicity of hormonally responsive mammary carcinomas. The fact that no synergistic or additive effects were observed in combination diet-treated rats raises the question of whether celecoxib is suitable for the prevention of hormonally nonresponsive breast cancer or for use in combination therapy with selective estrogen response modulators or aromatase inhibitors.

Not all selective estrogen response modulators are created equal: update on lasofoxifene

Not all selective estrogen response modulators are created equal: update on lasofoxifene

Changes in interneuronal phenotypes regulated by estradiol in the adult rat hippocampus: A potential role for neuropeptide Y

Ovarian hormones regulate pyramidal cell synapse formation and excitability and interneuronal GABAergic tone in the CA1 region of the adult female rat hippocampus. The role of 17β-estradiol in these effects is complex and appears to involve a subset of hippocampal interneurons, which express different calcium-binding protein and neuropeptide phenotypes and nuclear estrogen receptor α. We found that, in the hippocampus, nuclear estrogen receptor α-immunoreactive interneurons co-express neuropeptide Y, calbindin-D28k and calretinin but do not parvalbumin or cholecystokinin. Moreover, a proportion of neuropeptide Y-immunoreactive interneurons co-expresses calbindin-D28k and calretinin. This pattern is similar in the presence or absence of 17β-estradiol treatment in ovariectomized rats. We then used immunohistochemistry and in situ hybridization to determine whether 17β-estradiol treatment regulates expression of CA1 interneuronal phenotypic markers via nuclear estrogen receptor α activation. We found that 17β-estradiol treatment of ovariectomized rats increased neuropeptide Y mRNA levels (25%) and the neuropeptide Y mRNA-associated grain density per cell (11%), as well as the number of neuropeptide Y-immunoreactive cells (11%), predominantly in the pyramidal cell layer (stratum pyramidale). Treatment with CI628, a selective estrogen response modulator that acts as an antagonist for nuclear estrogen receptor, blocked 17β-estradiol-induced increase of neuropeptide Y mRNA levels. 17β-Estradiol treatment did not alter the number of parvalbumin, calretinin, and cholecystokinin immunoreactive cells, nor mRNA levels for parvalbumin and cholecystokinin. Therefore, the present study has identified neuropeptide Y expression as the main interneuronal phenotype that co-expresses nuclear estrogen receptor α and shown that neuropeptide Y is responsive to 17β-estradiol in CA1 pyramidal cell layer. We suggest that 17β-estradiol may regulate neuropeptide Y expression mediated by nuclear estrogen receptor α-dependent activation in a subset of hippocampal interneurons, and we speculate that subsequent neuropeptide Y release may indirectly contribute to regulate glutamate-dependent neuronal activity in the adult rat hippocampus.

Lasofoxifene (LASO), A Next Generation Selective Estrogen Response Modulator (SERM) Improves Dyspareunia in Postmenopausal Women with Vaginal Atrophy (VA)

Lasofoxifene (LASO), A Next Generation Selective Estrogen Response Modulator (SERM) Improves Dyspareunia in Postmenopausal Women with Vaginal Atrophy (VA)

Osteoporosis and breast cancer

Osteoporosis affects one in three women after the menopause and the incidence of osteoporotic fractures increases steadily throughout life. Breast cancer is the most common cancer in women, both before and after the menopause. In younger women, recovery from breast cancer has been achieved using aggressive chemotherapy and radiotherapy that can adversely affect bone tissue or induce premature menopause. In postmenopausal women, breast cancer and osteoporosis are common, and although both are dependent on estrogens this leads to conflicting implications for the diagnosis and treatment: estrogens reduce the risk of fractures but increase the risk of breast cancer. Estrogen supplementation is, therefore, contraindicated in patients with a history of breast cancer. Selective estrogen response modifiers (SERMs) hold great promise, as they decrease both the fracture risk via an estrogen-agonist effect on bone and the breast cancer risk via an estrogen-antagonist effect on the breast tissue. SERMs can be used after successful treatment for breast cancer. Bisphosphonates, which are potent bone resorption inhibitors, are widely used both in cancer patients and in the prevention and treatment of spinal and peripheral osteoporotic fractures. Contraindications are exceedingly rare, and the satisfactory safety profile of these agents can be expected to improve further with newly developed modes of administration. Whether the bisphosphonates currently used to treat osteoporosis (alendronate and risendronate) have beneficial effects on skeletal events related to cancer progression remains to be determined, however. In sum, selection of the optimal treatment for osteoporosis in a patient with breast cancer involves assessment of the risk/benefit ratio of each treatment option, based on patient age, other risk factors for osteoporosis, and the stage of breast cancer progression.

A phase II trial of arzoxifene, a selective estrogen response modulator, in patients with recurrent or advanced endometrial cancer

Objective The goal of this study was to determine response rate and evaluate toxicity of LY353381 (arzoxifene) in patients with recurrent or advanced endometrial cancer (EC). Methods A phase II, open-labeled study with arzoxifene was performed at 13 centers. Patients with measurable recurrent/advanced EC not amenable to curative therapies were eligible if either the primary tumor or recurrent tumor was ER+ and/or PR+. If receptor status could not be determined, patients with well or moderately well-differentiated EC were also permitted. Prior use of salvage chemotherapy was not allowed; however, prior use of progestagens was permitted and patients were stratified by prior exposure to progestagen. Patients received 20 mg/day PO, and were treated for at least 8 weeks in the absence of disease progression or unacceptable toxicity. Efficacy was based on the frequency of complete (CR) and partial (PR) responses, and a 95% confidence interval (CI) was calculated. The Kaplan–Meier method was used to analyze time to progression and duration of response. Results From February 1999 through April 2001, 37 patients were entered of whom 34 received treatment. Efficacy was evaluated for the 29 patients who received at least 4 weeks of therapy and at least one tumor response assessment. Safety was assessed in all 34 patients who received any drug. Thirty patients were defined as progestagen sensitive, and 4 patients were defined as progestagen failures. Twenty-six patients were ER+, and 22 were PR+. Nine (1 CR + 8 PR) of 29 patients responded (31%, CI 25–51%), with a median duration of response of 13.9 months. All 9 responses occurred in progestagen-sensitive patients. Two additional patients (one from each progestagen cohort) had stable disease for ≥6 months. The median progression-free interval was 3.7 months (CI 1.9–6.6 months) for all 29 patients. Toxicity was minimal with no grade 3–4 toxic effects, and 9 patients had only grade 1–2 toxic effects (7 grade 1, 2 grade 2). Hot flashes were the most common toxic effect and, in all 3 reported cases, were grade 1. Conclusions Arzoxifene has demonstrated a high response rate with the longest median duration of response reported in a phase II trial of this patient population. The ease of administration and extremely favorable toxicity profile make this an agent warranting further evaluation.