Coregulators in Nuclear Estrogen Receptor Action: From Concept to Therapeutic Targeting

Abstract

Estrogens are key regulators of growth, differentiation, and the physiological functions of a wide range of target tissues, including the male and female reproductive tracts, breast, and skeletal, nervous, cardiovascular, digestive and immune systems. The majority of these biological activities of estrogens are mediated through two genetically distinct receptors, ERalpha and ERbeta, which function as hormone-inducible transcription factors. Over the past decade, it has become increasingly clear that the recruitment of coregulatory proteins to ERs is required for ER-mediated transcriptional and biological activities. These "coactivator" complexes enable the ERs to respond appropriately: 1) to hormones or pharmacological ligands, 2) interpret extra- and intra-cellular signals, 3) catalyze the process of chromatin condensation and 4) to communicate with the general transcription apparatus at target gene promoters. In addition to activating proteins, the existence of corepressors, proteins that function as negative regulators of ER activity in either physiological or pharmacological contexts, provides an additional level of complexity in ER action. This review also describes current efforts aimed at developing pharmaceutical agents that target ER-cofactor interactions as therapeutics for estrogen-associated pathologies.

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…ERs recruit a plethora of cofactors in an agonist-dependent manner via both their N-terminal and C-terminal activation function regions (AF1 and AF2 respectively), including histone modifiers, chromatin remodeling complexes and components of the transcriptional machinery (Smith & O’Malley 2004, Hall & McDonnell 2005); (see also a list of known nuclear receptor coregulators at https://www.nursa.org/nursa/molecules/index.jsf, accessed on Aug. 15, 2016). The various ERα LBD conformations induced by different AEs affect protein–protein interaction interfaces (Wardell et al .…”

“…Among the coactivators interacting directly or indirectly with AF2 of the estradiol-bound ERα are the histone acetyl transferases NCOA1/2/3 (SRC-1/2/3), CBP/p300 and the histone methyl transferases CARM1, PRMT1 (Smith & O’Malley 2004, Hall & McDonnell 2005, Johnson & O’Malley 2012). In endometrial Ishikawa and ECC-1 cell lines, NCOA1 is recruited selectively to promoters of genes stimulated by tamoxifen, but not raloxifene; repressing NCOA1 expression in Ishikawa cells inhibits the partial agonist activity of tamoxifen on those target genes (Shang & Brown 2002).…”

Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways

“…However, a rapidly growing field offers a more complex view of gene transcription and emphasizes the importance of other molecules (including co-activators and co-repressors) in transcriptional regulation (Lai, 2002;Hall and McDonnell, 2005;Li et al, 2007;Yu and Reddy, 2007).…”

“…Growing evidence indicates that transcription factors require other molecules (for example, co-activators and repressors) to regulate their activities (Hall and McDonnell, 2005;Li et al, 2007;Yu and Reddy, 2007). In this review, we focus on the Mastermind-like (MAML) family of transcriptional co-activators that are integral to the Notch signaling pathway.…”

FOXP1, an Estrogen-Inducible Transcription Factor, Modulates Cell Proliferation in Breast Cancer Cells and 5-Year Recurrence-Free Survival of Patients with Tamoxifen-Treated Breast Cancer

“…The transcriptional activity of ERα is regulated by various coactivators and corepressors [2], as well as by interactions with other transcription factors, including the forkhead box (FOX) family. FOX family transcription factors influence ERα-regulated transcription by interaction with the ERα protein, as exemplified by FOXA1 [3].…”