Lewis JS, Jordan VC.. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res 591: 247-263

Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 3.68). 01/2006; 591(1-2):247-63. DOI: 10.1016/j.mrfmmm.2005.02.028
Source: PubMed


Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17beta-estradiol (E(2)), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERalpha or ERbeta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

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    • "Estrogens are sex steroid hormones, secreted by the ovaries and testis, and control a number of physiological actions including the development of female reproductive system and secondary characteristics, neuroendocrine actions involved in the control of ovulation, the cyclic preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein and lipid metabolism (Lewis and Jordan, 2005). These hormones also demonstrate remarkable effectiveness in deterrence and management of pre-and postmenopausal diseases (Rossouw et al., 2002; Yaffe et al., 1998). "
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    ABSTRACT: In this study, we explored the structural requirements of known estrogen receptor modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose, a group of nonsteroidal ligands 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives were collected from the literature to perform quantitative structure–activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (Ra 2 = 0.857, sea = 0.370, Qa 2 = 0.848, Rpred-a 2 = 0.675, spa = 0.537; Rb 2 = 0.874, seb = 0.261, Qb 2 = 0.859, Rpred-b 2 = 0.659, spb = 0.408) explained that hydrophobicity and molar refractivity were crucial for binding affinity in both a- and b-subtypes. The space modeling study (Ra 2 = 0.955, sea = 1.311, Qa 2 = 0.932, Rpred-a 2 = 0.737, spa = 0.497; Rb 2 = 0.885, seb = 1.328, Qb 2 = 0.878, Rpred-b 2 = 0.769, spb = 0.336) revealed the importance of HB donor and hydrophobic features for both subtypes, whereas HB acceptor and aromatic ring were critical for aand b-subtypes, respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking studies which provided the preferred orientation of ligands for effective interaction at the active site cavity.
    Full-text · Article · Jan 2016 · Medicinal Chemistry Research
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    • "ESR1 is a transcription factor that is routinely measured by immunohistochemical (IHC) assays to determine clinical ER status (ER-positive or ER-negative) and to guide endocrine therapy (Murphy & Watson 2002). Endocrine therapy is often deployed when primary tumours are classified as ER-positive and mostly revolves around the use of drugs that either block the estrogen growth stimulus directly at the level of ER (selective ER modulators/downregulators (SERMs/SERDs)) or indirectly by inhibition of estrogen production (aromatase inhibitors (AIs); Lewis & Jordan 2005, Cheang et al. 2008). The clinical designation, 'ER status' is based on assays that assess expression levels of only one ER, the classical ESR1. "
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    ABSTRACT: It is increasingly clear that inflammation-associated mechanisms can affect breast cancer progression and modulate response to treatment. Estrogen receptor alpha (ERα) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ERα positive at diagnosis and are candidates for endocrine therapy. However, ERα positive tumors can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed including ERα suppression. This review discusses the relationship between intratumoral inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ERα.
    Full-text · Article · Nov 2014 · Endocrine Related Cancer
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    • "The concept of SPPARMs (and other selective nuclear receptor modulators) was initially based on the paradigm of tamoxifen, a pioneering selective estrogen receptor modulator that exhibits anti-estrogenic activity in the mammary gland and partial pro-estrogenic activity in bone and uterus [38]. The observed increase in the incidence of uterine cancer with prolonged tamoxifen use led to the development of raloxifene, a second-generation estrogen receptor modulator with highly selective, tissue-specific activity that avoids uterotrophic effects. "
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    ABSTRACT: Dyslipidemia is a major risk factor for cardiovascular (CV) disease -- the primary cause of death, worldwide. Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk, a high level of residual risk persists, especially in people with obesity-related conditions, such as metabolic syndrome and type 2 diabetes mellitus. Peroxisome proliferator-activated receptor alpha- (PPARalpha-) agonists (e.g. fibrates), play a central role in the reduction of macro- and microvascular risk in these patients. However, the currently available fibrates are weak (PPARalpha-agonists) with limited efficacy due to dose-related adverse effects. To address this problem, a new generation of highly potent and selective PPARalpha-modulators (SPPARMalpha) is being developed that separate the benefits of the PPARalpha-agonists from their unwanted side effects. Among these, aleglitazar (a dual PPARalpha/gamma agonist) and GFT505 (a dual PPAR alpha/delta agonist) have recently entered late-phase development. Although both compounds are more potent PPARalpha-activators than fenofibrate in vitro, only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol (HDL-C) in humans. However, it is also associated with a potential risk of adverse effects. More recently, a highly potent, specific PPARalpha-agonist (K-877) has emerged with SPPARMalpha characteristics. Compared to fenofibrate, K-877 has more potent PPARalpha-activating efficacy in vitro, greater effects on triglycerides- and HDL-C levels in humans, and a reduced risk of adverse effects. If successful, K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes.
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