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Mechanisms of action of selective estrogen receptor modulators and down-regulators

Suzanne A.W. Fuqua, PhD
Rachel Schiff, PhD
Section Editor
Daniel F Hayes, MD
Deputy Editor
Sadhna R Vora, MD


About two-thirds of breast cancers express the estrogen receptor α (ER) protein. These ER-positive tumors are dependent on the ER and its cognate ligand, estrogen, for their growth, survival, and progression. Three major classes of endocrine therapy drugs, which differ by their basic mechanism of action, are in use for the treatment and/or prevention of ER-positive breast cancers. These therapies are all designed in one way or another to block ER function and signaling. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs), the focus of this topic, are competitive inhibitors of estrogen binding to ERs. How SERMs such as tamoxifen and raloxifene and SERM/SERD hybrid (SSH) agents can have both antagonist and agonist actions on the ER in different tissues and the distinctive mechanisms of action of SERDs such as fulvestrant and new oral SERDs will be reviewed here. The emphasis will be on the effects of tamoxifen and SERDs on breast cancer. Additional material on the physiology of estrogen and ERs is presented elsewhere. (See "Molecular biology and physiology of estrogen action".)

The third class of endocrine therapy agent, aromatase inhibitors, are discussed in detail elsewhere. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer" and "Treatment approach to metastatic hormone receptor-positive breast cancer: Endocrine therapy" and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)


Three agents are available that act as SERMs: tamoxifen, raloxifene, and toremifene [1]. All three agents are competitive inhibitors of estrogen binding to estrogen receptors (ERs), and all have mixed agonist and antagonist activity, depending on the target tissue. These mixed activities have led to the redesignation of this class of compounds from "anti-estrogens" to SERMs.

The mixed antagonist/agonist effect of SERMs on ERs can be illustrated by their physiological effects in postmenopausal women:

SERMs provide some protection against menopausal bone loss, presumably due to their partial agonist activity (figure 1 and figure 2) [2-5]. However, the increase in bone density is substantially less than that seen with estrogen therapy. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis".)


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