Selective estrogen receptor modulators: Structure, function, and clinical use

The sex harmone estrogen is important for many physiologic processes. Prolo nged stimulation of breast ductal epithelium by estrogen, however, can cont ribute to the development and progression of breast cancer, and treatments designed to block estrogen's effects are important options in the clinic. T amoxifen and other similar drugs are effective in breast cancer prevention and treatment by inhibiting the proliferative effects of estrogen that are mediated through the estrogen receptor (ER), However, these drugs also have many estrogenic effects depending on the tissue and gene, and they are mor e appropriately called selective estrogen receptor madulators (SERMs), SERM s bind ER, alter receptor conformation, and facilitate binding of coregulat ory proteins that activate or repress transcriptional activation of estroge n target genes. Theoretically, SERMs could be synthesized that would exhibi t nearly complete agonist activity on the one hand or pure antiestrogenic a ctivity on the other, Depending on their functional activities, SERMs could then be developed for a variety of clinical uses, including prevention and treatment of osteoporosis, treatment and prevention of estrogen-regulated malignancies, and even for hormone replacement therapy. Tamoxifen is effect ive in patients with ER-positive metastatic breast cancer and in the adjuva nt setting. The promising role for tamoxifen in ductal carcinoma-in-situ or for breast cancer prevention is evolving, and its use can be considered in certain patient groups. Other SEPMs are in development, with the goal of r educing toxicity and/or improving efficacy, and future agents have the pote ntial of providing a new paradigm for maintaining the health of women. (C) 2000 by American Society of Clinical Oncology.