Faculty Publications

Lewis JS, Jordan VC

Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance

Mutat Res. 2005;591(1-2):247-63.

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 17b-estradiol (E2), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERa or ERb, 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-pos. breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examd. the mol. 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) crit. 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. [on SciFinder (R)]