Molecular and cellular determinants of estrogen receptor alpha expression.

Abstract

Critical roles for estrogens in growth and development and in pathological conditions of bone, breast, and uterus are well established. Estrogens and estrogen receptor modulators bind to estrogen receptor α (ERα) and/or ERβ to form discrete molecular complexes that exert pleiotropic tissue-specific effects by modulating the expression of target genes. Ligand-bound ER functions as a key transcription factor in various molecular pathways, and modulation of ER expression levels is important in determining cellular growth potential. Recent advances have begun to illuminate the mechanisms by which cells control ER expression. Kos et al. reviewed the genomic organization of the human ERα gene promoter region (31). The human ERα gene, located on chromosome 6, was cloned in 1986 and spans approximately 300 kb; its eight coding regions are transcribed from at least seven promoters (31). Considering the complexity of the ER promoter, it is not surprising that numerous factors affect ERα expression. The aim of this paper is to review the molecular mechanisms by which various cellular factors modulate ERα expression. We have focused on highlighting the major players, including effectors of chromatin structure, hormones, and other relevant agents, and limited our discussion to findings in human systems. There are vast qualitative and quantitative data regarding whether or not, and to what extent, ERα is expressed in normal and neoplastic tissues; this topic is beyond the scope of this review and will not be covered. Moreover, little is currently known about the role of specific transcription factors in ER expression, and these factors will be mentioned only briefly. Henceforth, the terms ERα and ER will be used interchangeably; expression of ERβ will not be discussed.