Selective estrogen receptor modulators: tissue specificity and clinical utility

Abstract

Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs.

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…Tamoxifen, the first clinically approved SERM and the standard of care for the adjuvant treatment of all stages of primary breast tumors to this day (Jordan 2004, Ali et al . 2011, Martinkovich et al . 2014), has antagonist effects on breast cancer cell proliferation but has an estrogen-like action in bone in patients and in animal models, where it helps maintain bone mineral density in postmenopausal women, and has favorable agonist effects on lipid profiles (Turner et al .…”

“…1B) have been developed to increase treatment efficacy and decrease the negative side effects of tamoxifen, including the increase in the incidence of endometrial cancer and thromboembolic events and the generation of DNA adducts (see Martinkovich et al . 2014 for an in-depth review of the pharmacological properties of tamoxifen analogues).…”

“…However, these drugs are neither more efficacious than tamoxifen for breast cancer treatment nor do they circumvent resistance to tamoxifen in patients (Howell 2006, Ali et al . 2011, Martinkovich et al . 2014).…”

“…2010), but is not effective in patients resistant to tamoxifen (Ali et al . 2011, Martinkovich et al . 2014).…”

“…Promoter context is expected to affect partial agonist activity in a gene-specific manner either due to cofactor interaction with other DNA-bound transcription factors or to allosteric effects of the DNA sequence on the receptor conformation (Smith & O’Malley 2004, Johnson & O’Malley 2012). In addition, the relative expression levels of ERα and ERβ, the activity of signaling pathways leading to post-translational modifications of the receptors and/or their coregulators, and the extent of ERα downregulation may all contribute to the specific activity profiles of AEs (Smith & O’Malley 2004, Martinkovich et al . 2014).…”