Introduction, definitions and scope

The estrogen receptor (ER), including estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), mediates the biological effects of estrogen for the development and progression of breast cancer, and it serves as an important diagnostic and therapeutic target for prevention and treatment of breast cancer. Targeted estrogen-receptor therapy is the most successful strategy in breast cancer treatment and prevention. These endocrine therapies include aromatase inhibitors (AIs) indirectly targeting the ER that block the synthesis of estrogen from androgen in peripheral tissues and show efficacy in post-menopausal breast cancer patients. Another direct strategy is to use pure anti-estrogens (also called selective estrogen-receptor down-regulators, SERDs), such as fulvestrant, which have no agonist activity and cause degradation of the ER. Fulvestrant has been approved to treat advanced breast cancer after tamoxifen failure. The most widely used therapy for ER-positive breast cancer is selective estrogen receptor modulators (SERMs), which are synthetic molecules that bind to the ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the pioneering SERM, is extensively used for targeted therapy of ER-positive breast cancers, and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high-risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by a series of experiments in the laboratory that laid the foundation for its clinical use. Unfortunately, use of tamoxifen is associated with de novo and acquired resistance, and some undesirable side effects. The molecular study of resistance provides an opportunity to precisely understand the mechanism of action of SERMs, which may further help in designing new and improved SERMs. Clinical studies demonstrate that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as effective as tamoxifen in preventing breast cancer in post-menopausal women, but with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which can not only be used for therapy and prevention of breast cancer, but also for various other diseases and disorders. We will provide a basic background of anti-estrogens, the current utility of the two pioneering SERMs tamoxifen and raloxifene, discuss in detail the putative mechanism of action of SERMs, and consider progress with new SERMs.