Molecular and Cellular Determinants of Estrogen Receptor α Expression

Abstract

3Critical 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 ␣ (ER␣) and/or ER␤ to form discrete molecular complexes that exert pleiotropic tissue-specific effects by modulating the expression of target genes. Ligandbound 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 ER␣ gene promoter region (31). The human ER␣ 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 ER␣ expression. The aim of this paper is to review the molecular mechanisms by which various cellular factors modulate ER␣ 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, ER␣ 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 ER␣ and ER will be used interchangeably; expression of ER␤ will not be discussed.

Age-associated changes in bovine oocytes and granulosa cell complexes collected from early antral follicles

“…Together, these reports and the present results suggest that the differences in the developmental stage of the EAFs contribute to the differential responsiveness to E 2 . However, cellular responsiveness to E 2 is controlled by a complex mechanism that includes binding of ligand and receptors, activity of the receptor including phosphorylation by MAPK and CDC kinase [35,49], degeneration of ubiquitinated estradiol receptors by proteasome [50], methylation of estradiol receptor genes [51], and estradiol receptor localization [52]. Other possible mechanisms need to be examined.…”

Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

“…MCF-7 cells were cultured in Dulbecco's modified Eagle's medium (Invitrogen, Carlsbad, CA, USA). MDA-MB-231, HCC1937 and UACC3199cells were grown in RPMI 1640 medium (Invitrogen), and SK-BR3 cells were cultured in McCoy's 5a medium containing 1.5 mM of L-glutamine, 3.0 g/l glucose and 2.2 g/l sodium bicarbonate. All media were supplemented with 10% FBS.…”

“…Hormonal therapy via estrogen depletion or selective estrogen receptor modulators is widely used to block the action of estrogen in women with hormone-responsive breast cancers [1]. A potential mechanism for hormone resistance is the acquired loss of ER gene expression at the transcriptional level during disease progression [2,3]. Methylation of the CpG islands in the 5′ regulatory region of the ER gene has been associated with loss of ER gene expression in ER-negative breast cancers [4,5].…”

Reactivity of zinc finger cysteines: Chemical modifications within labile zinc fingers in estrogen receptor

“…T he 67 kDa human estrogen receptor (ER, alpha isoform) represents a critical transcription factor protein that mediates estrogen induced gene expression essential for normal reproductive gland development, the overexpression of which also drives the development of most human breast cancers and serves as the molecular target for all forms of breast cancer endocrine therapy [1,2]. Oxidative stress or chemical interference with either of the two Cys 4 -type zinc finger structures located within the ER DNA-binding domain (ER-DBD) may prevent its ability to directly bind DNA in a sequence-specific manner without impairing its ability to modulate gene expression by protein-protein interactions with other DNA-bound transcription factors [3,4].…”