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PubMed2001

Engineering of a mouse for the in vivo profiling of estrogen receptor activity.

In addition to their well known control of reproductive functions, estrogens modulate important physiological processes. The identification of compounds with tissue-selective activity will lead to new drugs mimicking the beneficial effects of estrogen on the prevention of osteoporosis and cardiovascular or neurodegenerative diseases, while avoiding its detrimental proliferative effects. As an innovative model for the in vivo identification of new selective estrogen receptor modulators (SERMs), we engineered a mouse genome to express a luciferase reporter gene ubiquitously. The constructs for transgenesis consist of the reporter gene driven by a dimerized estrogen-responsive element (ERE) and a minimal promoter. Insulator sequences, either matrix attachment region (MAR) or beta-globin hypersensitive site 4 (HS4), flank the construct to achieve a generalized, hormoneresponsive luciferase expression. In the mouse we generated, the reporter expression is detectable in all 26 tissues examined, but is induced by 17beta-estradiol (E2) only in 15 of them, all expressing estrogen receptors (ERs). Immunohistochemical studies show that in the mouse uterus, luciferase and ERs colocalize. In primary cultures of bone marrow cells explanted from the transgenic mice and in vivo, luciferase activity accumulates with increasing E(2) concentration. E2 activity is blocked by the ER full antagonist ICI 182,780. Tamoxifen shows partial agonist activity in liver and bone when administered to the animals. In the mouse system here illustrated, by biochemical, immunohistochemical, and pharmacological criteria, luciferase content reflects ER transcriptional activity and thus represents a novel system for the study of ER dynamics during physiological fluctuations of estrogen and for the identification of SERMs or endocrine disruptors.

Animals↗
PubMed2003

Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary- adrenal axis in female monkeys.

The selective estrogen receptor modulator, tamoxifen, effectively slows the progression of estrogen-positive breast cancer and reduces the possibility of this cancer developing in women at high risk. Despite the widespread acceptance of tamoxifen as a therapeutic agent for this disease, its effects on other estrogen-dependent pathways, particularly on neural circuits regulating brain function and peripheral hormone secretion, are poorly understood. The present study, using previously ovariectomized rhesus monkeys, examined the effects of tamoxifen, in both the presence and absence of estradiol replacement, on the reproductive and hypo-thalamic-pituitary-adrenal (HPA) axes. In Experiment 1, monkeys randomly assigned to three groups (n = 8 each) were treated with placebo and either two doses of estradiol, two doses of tamoxifen alone, or two doses of tamoxifen plus high-dose estradiol to assess the effects on negative feedback suppression of luteinizing hormone (LH). Both doses of tamoxifen effectively antagonized the negative feedback efficacy of estradiol on LH secretion. In contrast, neither the low- or high-dose tamoxifen alone had any effect on LH secretion, as concentrations during tamoxifen treatments were indistinguishable from those during placebo. In Experiment 2, females were randomly assigned to one of four treatment groups (placebo, n = 6; estradiol, n = 5; tamoxifen only, n = 5; or tamoxifen plus estradiol, n = 6) to assess the effects on glucocorticoid negative feedback and pituitary and adrenal responsiveness to exogenous corticotropin- releasing hormone (CRH). Tamoxifen also antagonized the facilitating effects of estradiol on basal and CRH-induced ACTH and cortisol secretion. However, this antagonism produced basal and CRH-stimulated cortisol and ACTH concentrations that were lower than placebo-treated females. Interestingly, tamoxifen in the absence of estradiol produced a similar diminution in ACTH and cortisol response. These data suggest that, in the presence of estradiol, tamoxifen not only antagonized estrogenic facilitation of HPA responsivity but also actually attenuated the response compared with the placebo-treatment condition. Taken together, these data indicate that tamoxifen acts as an estrogen antagonist on the neural circuits controlling the neuroendocrine regulation of the hypothalamic-pituitary-ovarian and adrenal axes in ovariectomized macaque females.

Adrenocorticotropic Hormone↗
PubMed2004

Cardiovascular effects of raloxifene: the arterial and venous systems.

BACKGROUND: Cardiovascular disease caused by atherosclerosis is the largest single killer of women. Prior observational data had suggested that hormone therapy may have cardioprotective effects. METHODS: Data from clinical trials and basic science studies were evaluated to assess the cardiovascular effects of hormone therapy and selective estrogen replacement modulators. RESULTS: Hormone therapy does not appear to lower the risk of cardiovascular events in older postmenopausal women. Selective estrogen receptor modulators (SERMS) have been approved for human use; tamoxifen is used for treatment and prevention of breast cancer and raloxifene is used for the treatment and prevention of osteoporosis. Raloxifene is the only SERM being specifically studied for its effects on coronary heart disease events in a prospective, randomized, controlled trial. CONCLUSIONS: Although raloxifene does increase venous thromboembolic events, there is suggestive data that it may have favorable effects on the arterial systems in women. Only compelling positive data from the Raloxifene Use for The Heart (RUTH) trial will lead to greater use of SERMS to potentially lower the risk of atherosclerotic vascular disease.

Arteries↗
PubMed2004

[Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies].

Estrogen replacement therapy, in spite of efficacy in the prevention of osteoporotic fractures, has significant side effects and risks that limit its widespread usage in postmenopausal women. Thus significant medical need exists to find modalities that prevent osteoporosis, but without the side effects of estrogen. Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Tamoxifen, a first generation SERM is approved for the prevention and treatment of breast cancer, and raloxifene, a second generation SERM has been approved for the prevention and treatment of osteoporosis. Lasofoxifene, a new potent, nonsteroidal SERM, binds with high affinity to human estrogen receptors and acts as a tissue selective estrogen antagonist or agonist. In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton. In studies designed to investigate the combination of lasofoxifene with estrogen, lasofoxifene blocked the hypertrophic effects of estrogen in the uterus, but did not block the bone protective effects. In immature and aged female rats, lasofoxifene did not affect the uterine weight and uterine histology. In preclinical studies designed to evaluate the effects of lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight suggesting that the increased uterine weight was due to increased water content in the tissue. In preclinical studies designed to evaluate the effects of lasofoxifene in breast cancer, lasofoxifene inhibited breast tumor formation in mice injected with human MCF-7 breast cancer cells and in rats bearing mammary carcinomas. Thus, in preclinical models, lasofoxifene, a next generation SERM, prevents estrogen deficiency-induced bone loss, inhibits breast tumor formation, and reduces serum cholesterol, without causing uterine hypertrophy. These data suggest that lasofoxifene is a new potential therapy for the prevention of osteoporosis in postmenopausal women.

Animals↗
PubMed2004

Raloxifene modulates interleukin-6 and tumor necrosis factor-alpha synthesis in vivo: results from a pilot clinical study.

Raloxifene (RAL), a selective estrogen receptor modulator, is indicated for the prevention and treatment of postmenopausal osteoporosis. RAL, by decreasing bone turnover, prevents bone loss and microarchitecture damage, reducing the incidence of osteoporotic fractures. Our previous in vitro data demonstrated that RAL modulates osteoclast activity by, at least in part, an IL-6- and TNF-alpha-dependent mechanism. In this study we evaluated the effects of RAL treatment (60 mg/d) on circulating levels of these cytokines in 14 postmenopausal women with osteoporosis. Lumbar bone density (determined by dual energy x-ray absorptiometry) and IL-6 and TNF-alpha levels were measured before and after 6 and 24 months of therapy. After 24 months, RAL increased bone density. IL-6 and TNF-alpha expression, elevated before treatment, significantly decreased (50% and 30%, respectively) after 6 months. This effect was sustained up to the end of the treatment (75% and 35%, respectively). Thus, our data show that RAL can modulate circulating levels of cytokines involved in osteoclastogenesis and bone resorption, suggesting that modulation of soluble factors could play a pivotal role in the mechanisms of the osteoprotective effect of RAL.

Bone Density↗
PubMed2005

Seladin-1 as a target of estrogen receptor activation in the brain: a new gene for a rather old story?

Experimental evidence indicates that estrogen exerts neuroprotective effects. According to the fact that Alzheimer's disease (AD) is more common in post-menopausal women, estrogen treatment has been proposed. However, the beneficial effect of estrogen or selective estrogen receptor modulators (SERMs) in preventing or treating AD is a controversial issue, which will be summarized in this review. Recently, a novel gene, named selective AD indicator-1 (seladin-1), has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1, which is considered the human homolog of the plant protein DIMINUTO/DWARF1, confers protection against beta-amyloid-mediated toxicity and from oxidative stress and is an effective inhibitor of caspase 3 activity, a key mediator of apoptosis. This review will present the up-to-date findings regarding seladin-1 and DIMINUTO/DWARF1. In addition, the possibility that seladin-1 may be a downstream effector of estrogen receptor activation in the brain, based on our recent experimental findings using a human fetal neuronal model, will be addressed.

Alzheimer Disease↗
PubMed2000

Tamoxifen and mammographic breast densities.

The extent of breast tissue density on mammograms is one of the strongest risk factors for breast cancer. The aim of this analysis was to evaluate whether tamoxifen can affect mammographic breast density. Subjects were participants in the National Surgical Adjuvant Breast Project Breast Cancer Prevention Trial (BCPT), recruited and followed at the Breast Center of Saint-Sacrement Hospital in Quebec City, Canada. The Breast Cancer Prevention Trial is a double-blind trial in which women at high risk of breast cancer were randomized to receive either 20 mg tamoxifen per day or placebo. Mammograms were taken before treatment began and yearly thereafter. For the purpose of this analysis, Wolfe's parenchymal pattern and the percentage of the breast showing tissue densities were assessed by review of pre- and posttreatment mammograms without knowledge of treatment assignment. Among the 69 women included in this analysis, 36 received tamoxifen and 33 received placebo for an average of 3.3 and 3.5 years, respectively. Among women receiving tamoxifen, 16 of 36 (44.4%) changed to a parenchymal pattern of lower density compared with 5 of 33 (15.2%) women receiving placebo (P = 0.010). Moreover, in the tamoxifen-treated group, the difference in the percentage of the breast showing tissue densities between the pre- and posttreatment mammograms reached -9.4% on average compared with a reduction of -3.6% in the placebo group (P = 0.010). Our data show that tamoxifen can reduce high-risk mammographic features. Breast densities should be evaluated as possible early markers of the preventive effect of selective estrogen receptor modulators.

Adult↗
PubMed2006

Prevention of breast cancer: current state of the science and future opportunities.

Despite significant progress in breast cancer treatment, mammary tumours still represent the second most frequent cause of cancer-related death in women in the US, with > 211,000 new cases in 2005; however, an expanding range of options for early diagnosis and more reliable risk assessment offers new alternatives for disease control by cancer prevention. Completed large studies with the classical selective estrogen receptor modulator (SERM) tamoxifen have demonstrated that preventing breast cancer pharmacologically is now possible. Novel SERMs, aromatase inhibitors and gonadotropin-releasing hormone agonists targeting hormonal pathways are being tested in clinical trials, revealing the potential for dramatic reductions in tumour incidence with minimal side effects; however, SERMs and aromatase inhibitors are effective only against estrogen receptor-positive tumours, thus chemopreventive drugs targeting other critical signalling pathways (such as retinoids, selective COX inhibitors and tyrosine kinase inhibitors) may provide a means to prevent estrogen receptor-negative breast cancer. In the future, hormonal and estrogen receptor-independent agents may be combined to prevent the development of all mammary tumours. This article reviews the current and novel strategies for breast cancer prevention.

Adenocarcinoma↗
PubMed1999

The evolving role of specific estrogen receptor modulators (SERMs)

Estrogens are the most effective therapy for women with postmenopausal problems. However, relatively few women use estrogen and then often for a limited time because of the fear of its carcinogenic effects on the uterus and breast; in addition, estrogen is not advised for women who have had breast cancer. Selective estrogen receptor modulators (SERMs) are agents with antagonist action on the uterus and breast and agonist action on the bones, cardiovascular system, and brain. Unlike estrogens, however, existing SERMs do not help alleviate the vasomotor and urogenital problems associated with menopause. A comprehensive review of the literature published from January 1995 to June 1999 was conducted. Reports were identified using Medline and Cancer Lit. The effect of menopausal problems on the health of women and the socioeconomic effects of menopause are discussed. All currently available and investigational SERMs are reviewed and discussed, including their mechanism of action, metabolism, dose scheduling, antitumor activity, and potential role in maintaining the health of menopausal women and in preventing breast cancer.

Aged↗
PubMedDate not supplied

Assessment of hormonally active agents in the reproductive tract of female nonhuman primates.

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks-3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents.

Animals↗
PubMed2005

[Idiopathic and secondary osteoporosis in childhood].

Osteoporosis is a common disease characterized by reduced bone mass, with a consequent increase in bone fragility and susceptibility to fracture risk. Bone mineral density (BMD) measurement is used to make the diagnosis of osteoporosis prior to incident fracture, and to predict fracture risk. BMD is determined by the peak bone mass achieved, and the rate and timing of subsequent bone loss. Dual-energy X-ray absorptiometry (DEXA) is the most popular and effective method utilized for osteoporosis screening. Bone disease is a side effect of concern regarding chronic glucocorticoid (GC) administration. Most GC-treated patients exhibit a process of bone loss, frequently leading to osteoporosis, with increased fracture risk, especially in spinal vertebrae. Osteogenesis imperfecta is an inherited and generalized connective tissue disorder characterized mainly by bone fragility. Idiopathic osteoporosis of childhood or adolescence without blue sclerae and other stigmata of osteogenesis imperfecta is occasionally observed and sometimes more than one sib is affected. Beta-thalassemia major is associated with significant bone disease. The etiology of the bone disease is still debatable, many factors can adversely affect bone accretion in thalassemic patients. These include delayed puberty, bone marrow expansion, the deleterious effects of desferrioxamine, iron overload and genetic factors. Current treatment alternatives of osteoporosis include bisphosphonates, calcitonin, and selective estrogen receptor modulators.

Absorptiometry, Photon↗
PubMed2006

Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions.

BACKGROUND: Melatonin exerts oncostatic effects on different kinds of tumors, especially on endocrine-responsive breast cancer. The most common conclusion is that melatonin reduces the incidence and growth of chemically induced mammary tumors, in vivo, and inhibits the proliferation and metastatic behavior of human breast cancer cells, in vitro. Both studies support the hypothesis that melatonin oncostatic actions on hormone-dependent mammary tumors are mainly based on its anti-estrogenic actions. METHODS AND RESULTS: Two different mechanisms have been proposed to explain how melatonin reduces the development of breast cancer throughout its interactions with the estrogen-signaling pathways: (a) the indirect neuroendocrine mechanism which includes the melatonin down-regulation of the hypothalamic-pituitary reproductive axis and the consequent reduction of circulating levels of gonadal estrogens and (b) direct melatonin actions at tumor cell level. Melatonin's direct effect on mammary tumor cells is that it interferes with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator. Melatonin also regulates the activity of the aromatases, the enzymes responsible for the local synthesis of estrogens, thus behaving as a selective estrogen enzyme modulator. CONCLUSIONS: The same molecule has both properties to selectively neutralize the effects of estrogens on the breast and the local biosynthesis of estrogens from androgens, one of the main objectives of recent antitumor pharmacological therapeutic strategies. It is these action mechanisms that collectively make melatonin an interesting anticancer drug in the prevention and treatment of estrogen-dependent tumors, since it has the advantage of acting at different levels of the estrogen-signaling pathways.

Animals↗
PubMed2002

Chemoprevention of prostate cancer: current status and future directions.

Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.

Anticarcinogenic Agents↗
PubMed2006

Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases.

Peroxisome Proliferator Activated Receptors (PPARs) are regulators of metabolic pathways mainly of lipid metabolism and energy balance. Their medical importance is given by the fact that they have been implicated in development of insulin resistance, obesity and atherosclerosis. In recent years, major progress has been made in understanding the molecular basis of the function of these receptors. As a result of structural studies and identification of putative natural as well as synthetic ligands and activators of PPARs a new concept emerged and new drugs are on their ways to the clinic. The concept of Selective PPAR Modulators (SPPARM) was suggested by analogy to Selective Estrogen Receptor Modulators (SERM). SPPARMs activate the receptors in distinct ways leading to differential gene expression and biological response. The key features in understanding their action is most likely at the molecular details of ligand binding and the subsequently induced conformational changes as well as cofactor binding. A key aspect of this is that unlike classical steroid hormone receptors such as the retinoic acid receptor, the PPAR receptors have a rather large ligand-binding pocket which is not filled with the ligand entirely and the ligand also stabilizes the receptor's structure. The liganded receptor can have distinct conformations and this leads to different binding affinities for the various cofactors (coactivators and corepressors). In this review, we will introduce this concept, review the literature that supports it and present an overview of the receptor selective ligands including data about their mechanism of action and biological effects.

Animals↗
PubMed2001

Effects of estrogen deficiency on brain function. Implications for the treatment of postmenopausal women.

A growing body of evidence suggests that postmenopausal estrogen deficiency accelerates brain aging and increases the risk of various neurodegenerative processes, including Alzheimer's disease. Recent preclinical and clinical studies have indicated that estrogen has positive effects on brain homeostasis by preserving neural plasticity and the neurotransmitter pathways involved in learning, memory, and balance. In this article, Dr Birge and his coauthors address the effects of estrogen on brain function and discuss their implications for the use of selective estrogen receptor modulators, particularly tamoxifen and raloxifene, in postmenopausal women.

Aging↗
PubMed2004

Characterization of new estrogen receptor destabilizing compounds: effects on estrogen-sensitive and tamoxifen-resistant breast cancer.

BACKGROUND: Antiestrogens of the selective estrogen receptor modulator (SERM) type, such as tamoxifen, have two major limitations: their mixed agonist and antagonist profile and the development of tumor resistance. We characterized two new pure antiestrogens-ZK-703 and ZK-253-that belong to the class of specific estrogen receptor destabilizers (SERDs), which includes fulvestrant, and compared their activity with that of fulvestrant and tamoxifen. METHODS: Effects of antiestrogens on the growth of estrogen-dependent breast tumors in vivo were determined using several mouse xenograft models (including the tamoxifen-sensitive tumors MCF7, T47D, and MV3366 and the tamoxifen-resistant tumors ZR75-1 and MCF7/TAM) and chemically induced (nitrosomethyl urea [NMU] and dimethylbenzanthracene [DMBA]) rat breast cancer models (groups of 10 animals). We determined the initial response and effects on hormone receptor levels and the time to relapse after treatment (i.e., time to reach a predetermined tumor size threshold). Estrogen receptor (ER) levels were determined by immunoassay. RESULTS: ZK-703 (administered subcutaneously) and ZK-253 (administered orally) were more effective than tamoxifen or fulvestrant at inhibiting the growth of ER-positive breast cancer in all xenograft models. For example, MCF7 tumors relapsed (i.e., reached the size threshold) in 10 weeks in mice treated with tamoxifen but in 30 weeks in mice treated with ZK-703. ZK-703 and ZK-253 also prevented further tumor progression in tamoxifen-resistant breast cancer models to a similar extent (more than 30 weeks in mice with ZR75-1 and MCF7/TAM tumors). In the chemically induced rat breast cancer models, orally administered ZK-703 and ZK-253 caused a nearly complete (>80%) inhibition of tumor growth. ER levels were dramatically reduced in MCF7 tumors after 5 weeks of ZK-703 treatment compared with ER levels in vehicle-treated tumors; by contrast, ER levels in tamoxifen-treated tumors were higher than those in control tumors. CONCLUSION: ZK-703 and ZK-253 are potent, long-term inhibitors of growth in both tamoxifen-sensitive and tamoxifen-resistant breast cancer models.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity.

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology does not result from tissue-selective deconjugation of metabolite to parent.

Adenocarcinoma↗
PubMed2004

Coregulator function: a key to understanding tissue specificity of selective receptor modulators.

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

Animals↗