Cooperating transcription factors mediate the function of estrogen receptor

Abstract

Estrogen receptor (ER) is a hormone-regulated transcription factor that controls cell division and differentiation in the ovary, breast, and uterus. The expression of ER is a common feature of the majority of breast cancers, which is used as a therapeutic target. Recent genetic studies have shown that ER binding occurs in regions distant to the promoters of estrogen target genes. These studies have also demonstrated that ER binding is accompanied with the binding of other transcription factors, which regulate the function of ER and response to anti-estrogen therapies. In this review, we explain how these factors influence the interaction of ER to chromatin and their cooperation for ER transcriptional activity. Moreover, we describe how the expression of these factors dictates the response to anti-estrogen therapies. Finally, we discuss how cytoplasmatic signaling pathways may modulate the function of ER and its cooperating transcription factors.

The Cellular Mastermind(?)—Mechanotransduction and the Nucleus

“…Histones are well suited to transmit signals directly to the genome through a plethora of covalent biochemical modifications such as acetylation, phosphorylation, methylation, poly-ADP-ribosylation, ubiquination, and SUMOylation which affect the structure and transcriptional activity of chromatin without altering the DNA sequence. 10,11 Broadly speaking, chromatin exists in two states, (1) the more transcriptionally active, more loosely organized euchromatin, which typically localizes to central regions of the nucleus, and (2) the transcriptionally inactive, more densely packed heterochromatin, which inhabits the nuclear periphery and the area surrounding nucleoli. 12 DNA-binding dyes such as DAPI or Hoechst stain compact heterochromatin darker than its euchromatic counterpart.…”

“…46 In contrast, lamin A undergoes an additional modification, where the protein Zmpste24 removes the farnesylated tail, resulting in mature lamin A. Lamin C, which has a distinct C-terminus, does not undergo the same processing and is not farnesylated. 10 Mature lamin A and lamin C, which lack the hydrophobic farnesyl tail, can be found both in the nucleoplasm and the nuclear lamina. 47 …”

“…For a detailed discussion of lamin binding partners and their function, we refer to a recent review by Simon and Wilson. 10 …”

“…182 For lamins and other nuclear envelope proteins, which can also undergo various posttranslational modifications, the functional consequences and prevalence of such modifications outside of their role in mitosis are only beginning to emerge and are likely to produce exciting new insights. 10,63 …”

Prediction of Response to Aromatase Inhibitors in Breast Cancer

“…The proliferative effects of oestrogens in breast cancer cells are mediated through oestrogen receptors, which are ligand-dependent nuclear transcription factors, regulating expression of oestrogen-dependent genes [59]. Studies in a variety of clinical settings have demonstrated the clinical utility of oestrogen receptor as a molecular predictor for hormone response.…”