TY - JOUR
T1 - Selective estrogen receptor modulators (SERMs)
T2 - Mechanisms of anticarcinogenesis and drug resistance
AU - Lewis, Joan S.
AU - Jordan, V. Craig
N1 - Funding Information:
The work described was supported by DOD Training Grant in Breast Neoplasia DAMD17-00-1-0386, Training Program in Signal Transduction T32 CA70085-06, SPORE in Breast Cancer P50 CA89018-03, Lynn Sage Breast Cancer Research Foundation, and The Avon Foundation.
PY - 2005/12/11
Y1 - 2005/12/11
N2 - 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 17β-estradiol (E2), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERα or ERβ, 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.
AB - 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 17β-estradiol (E2), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERα or ERβ, 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.
KW - Breast cancer
KW - Estrogen
KW - Estrogen receptor
KW - Raloxifene
KW - Selective estrogen receptor modulator
KW - Tamoxifen
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U2 - 10.1016/j.mrfmmm.2005.02.028
DO - 10.1016/j.mrfmmm.2005.02.028
M3 - Article
C2 - 16083919
AN - SCOPUS:27844511538
SN - 0027-5107
VL - 591
SP - 247
EP - 263
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
IS - 1-2
ER -