Selective Estrogen Receptor Modulators as Therapeutic Agents in Breast Cancer Treatment

Abstract

Breast cancer is the most commonly diagnosed cancer in women of the Western world. Breast tumors are initially dependent upon estrogens for their growth. Drugs with antiestrogenic activity, e.g., tamoxifen, are used clinically both to prevent and treat breast cancer. Estrogens stimulate breast cancer cell proliferation by binding to estrogen receptors alpha and beta (ERα and ERβ) that are ligand-activated transcription factors. Estrogen-activated ER either binds directly to DNA sequences called estrogen response elements (EREs), or interacts with other DNA-bound transcription factors in the promoters of target genes to regulate transcription. Selective estrogen receptor modulators (SERMs) compete with estrogens for binding ER and act as a mixed ER agonist/antagonists depending on the cell type, e.g., antiestrogenic in breast and estrogenic in bone. Examples of SERMs in current clinical use are tamoxifen and raloxifene. This chapter discusses the effect of SERMs on the structure and function of ERα and ERβ. Structural studies indicate that ER occupied by SERMs has a different conformation from estradiol-occupied ER. This structural difference prevents the interaction of SERM-occupied ER with coactivator proteins necessary for chromatin remodeling involved in the initiation of gene transcription. Instead, SERM-occupied ER interacts with the corepressors NCoR and SMRT in vitro and when SERM-occupied ER is bound to ERE-containing genes in breast cancer cells. Corepressors interact with histone deacetylase (HDAC) complexes that maintain chromatin in a repressed state that precludes initiation of target gene transcription. Recent data from chromatin immunoprecipitation assays indicate that SERM-occupied ERα interacts with coactivators when tethered to the promoters of AP-1-regulated estrogen target genes in endometrial cancer cells, thus providing a mechanism for the agonist activity of tamoxifen in endometrial cells. The applicability of these findings to other cell types in which tamoxifen has agonist activity remains to be determined.