Article

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

ABSTRACT

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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    • "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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    • "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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