Estrogen Receptor-β Isoforms and Coactivators in Breast Cancer: Comparison
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Please note this is a comparison between Version 1 by Young Choi and Version 2 by Catherine Yang.

Nuclear receptor coregulators are the principal regulators of Estrogen Receptor (ER)-mediated transcription. ERβ, an ER subtype first identified in 1996, is associated with poor outcomes in breast cancer (BCa) subtypes, and the coexpression of the ERβ1 isoform and AIB-1 and TIF-2 coactivators in BCa-associated myofibroblasts was associated with high-grade BCa. Thus, this rwesearch aimed to identify additional coactivators that are involved in the progression of ERβ-expressing BCa. ERβ isoforms, coactivators, and prognostic markers were tested using standard immunohistochemistry. AIB-1, TIF-2, NF-kB, p-c-Jun, and/or cyclin D1 were differentially correlated with ERβ isoform expression in the BCa subtypes and subgroups

  • estrogen receptor β
  • coactivator
  • correlation
  • coregulation

1. Two Estrogen Receptors

There are two estrogen receptor (ER) genes (ESR1/ERα and ESR2/ERβ). ERα and ERβ are members of the nuclear receptor superfamily of transcription factors and share some structural similarities, including a high degree of homology (96%) in their DNA-binding regions. However, they also have distinct differences in genotype, tissue distribution, and binding to pharmacological agents; they share only moderate homology in the ligand-binding region, and they have markedly distinct NH2-terminal activation function-1 (AP-1) regions. ERα and ERβ can form heterodimers [1]; when coexpressed, ERβ acts as a transdominant inhibitor of ERα transcriptional activity. Thus, the relative levels of ERα and ERβ in breast cancer (BCa) are likely to affect cell proliferation, signaling pathways, and their response to ER ligands [2][3]. ERβ has different variant forms that interact with multiple protein partners, as well as ligands, and heterodimerize with ERα, thereby creating a highly complex labyrinth of functions. Furthermore, ERβ localizes in different cellular compartments and is susceptible to different posttranscriptional modifications (PTM) [4][5][6].
The exact role of ERβ in BCa has not yet been fully established. Highly variable and even opposite effects have been ascribed to the expression of ERβ isoform mRNA and protein expression in BCa, including both proliferative and growth-inhibitory actions, as well as favorable or adverse clinical outcomes [7][8]. ERβ1 protein expression is associated with poor prognostic markers [9]. ERβ2 and ERβ5mRNA expression are risk factors for OS in BCa subtypes and are associated with poor prognostic biomarkers, particularly in ERα-negative BCa and TNBC [10]. Overall, the outcome results of ERβ expression in BCa are inconsistent. Such inconsistent and controversial results may be due to the complexity of ERβ isoforms and the lack of standardized testing protocols but may also relate to various downstream signaling pathways, their PTM, and the their involvement of coregulators in its transcription.

2. Nuclear Receptor Coregulators

Nuclear receptor (NR) coregulators have emerged as the principal regulators of gene expression by directly interacting with and modulating the activity of NRs. ER-mediated transcriptional and biological activities require the recruitment of a diverse array of coregulator proteins to ERs. Coregulator complexes enable the ERs to respond to hormones or pharmacological ligands and communicate with the transcription apparatus at target gene promoters. Ligand-dependent and ligand-independent ERα and ERβ receptors recruit coactivators and corepressors and activate or repress ER-mediated transcription [11][12][13][14][15]. Alterations in ER conformation induced by binding to different estrogen response element (ERE) sequences modulate ERα and ERβ interaction with coactivators and corepressors [16].
Steroid receptor coactivator (SRC) family members, the p160 class, of coactivators are a gene family characterized as the primary coactivators for NRs and are required for NR-mediated transcription. They have been widely implicated in the regulation of steroid hormone action by mediating functions of NRs and facilitating the assembly of transcriptome complexes at target genes [14][17][18]. The SRC family consists of three members: SRC-1 (NCOA1), transcriptional intermediary factor-2 (TIF-2/SRC-2/GRIP-1/NCOA2), and amplified in breast cancer-1 (SAIB-1/SRC-3/NCOA3). The alteration or deregulation of SRC coregulators is common in BCa and enhances both ligand-independent and ligand-dependent ERα signaling to drive the proliferation, progression, and invasive capacity of neoplastic cells [13][14][15][19].
Among the SRC family members, SRC-3/AIB-1 is the primary coactivator for ERα and is overexpressed in BCa, and it is a crucial driver of mammary tumorigenesis [20][21][22][23][24]. AIB-1 mRNA and protein overexpression correlate with the expression of high Her2/neu, larger tumor size, higher tumor grade, and poor disease-free survival (DFS). AIB-1 also interacts with coactivates p65/NF-κB and plays an essential role in the NF-kB signaling pathway [17][25]. Furthermore, AIB-1 facilitates the transition of downstream genes encoding cyclin D1 and the insulin-like growth factor-1 (IGF1) pathway [14][18][19], and it promotes the epithelial–mesenchymal transition through its interaction with ERα and worse outcomes in Erα-positive BCa [19][26]. In tamoxifen (TAM)-treated patients, high AIB-1 expression is associated with TAM resistance and poorer DFS [19][27][28][29]. The overexpression of AIB-1 correlated with poor prognosis in TNBC patients [19][30].
TIF-2 is frequently overexpressed in various neoplasms. Recurrent prostate cancers have exhibited high expression levels of THE androgen receptor, TIF-2, and SRC-1 [31]. TIF-2 correlates significantly with lymph node (LN)-positive BCa [32].
SRC-1 frequently correlates with high Her2/neu expression, LN metastasis, disease recurrence, poor DFS, and more advanced disease stage in BCa [33][34]. SRC-1 is a coactivator that can switch BCa from a steroid-responsive to a steroid-resistant state and promote the aggressive BCa phenotype. It has been implicated in aromatase inhibitor-resistant recurrent BCa [35]. SRC-1 and its homolog transcriptional co-activators p/CIP have been shown to be the coactivators for NF-kB, CREB, and STAT-1 [36].
NF-kB is a pleiotropic transcription factor and is the key activator of genes involved in host immunity and inflammatory responses with the induction of a large number of genes that influence cellular proliferation and inflammation. NF-kB activity promotes tumor proliferation, regulates cell apoptosis, and also induces the epithelial–mesenchymal transition, which facilitates distant metastasis and transactivates the expression of cyclin D1 and c-myc [37][38].
C-Jun is a component of the transcription factor AP-1. Extra- or intracellular signals, including growth factors and transforming oncoproteins, stimulate the phosphorylation of c-Jun at serine 63/73 and activate c-Jun-dependent transcription. Activated c-Jun has been demonstrated to be associated with proliferation and angiogenesis [39], as well as epithelial stem cell expansion [40].
Cyclin D1 is frequently overexpressed in BCa and contributes to ERα activation in BCa. AIB-1 and other steroid receptor coactivators can enhance the functional interaction of ERα with the cyclin D1 promoter [41], while cyclin D1 can recruit SRC-1 and AIB-1 to ERα in the absence of a ligand [42]. High cyclin D1 expression is associated with high proliferation and a higher risk of death from BCa in ERα-positive BCa. However, no significant prognostic impact of cyclin D1 expression has been found among ERα-negative cases [43], and the reverse relationship was demonstrated for cyclin D1 overexpression in invasive ductal carcinoma [44].

Overall, ERα-coactivator proteins enhance ligand-dependent and ligand-independent ERα signaling, progression, endocrine therapy resistance, and metastasis in BCa. Suen et al. [45] demonstrated that AIB-1 selectively enhances ERα but does not enhance ERβ-dependent gene transcription. TAM-induced AIB-1 recruitment to the ER-ERE enhanced interaction between AIB-1 and ERα but not ERβ. However, Liu et al. [46] observed opposing actions of ERα and ERβ with the dominance of ERβ over ERα in the activation of cyclin D1 gene expression. Estrogens, which activate cyclin D1 gene expression with ERα, inhibit expression with ERβ. The different recruitments of AIB-1 to ERα and ERβ may, in part, explain the different associations between ERs and response to endocrine treatment [47].Further, Bai et al. [48] observed that both ERα and ERβ can interact with the coactivator receptor interaction domains (RIDs) of all three SRC isoforms in living cells. Other studies have also demonstrated that ERβ transactivation recruits members of the SRC family [49][50]. The phosphorylation of AF-1 by MAP kinase (MAPK) leads to the recruitment of SRC-1 by ERβ and provides a molecular basis for the ligand-independent activation of ERβ via the MAPK cascade [51]. ERβ expression was significantly correlated with SRC-1, TIF-2, and NCOR protein levels in BCa and the upregulation of expression levels of ERβ and cofactors during the development of intraductal carcinomas [32]. ERβ and GRIP1/TIF2 has been shown to interact in vitro in a ligand-dependent manner and the transcriptional responses to estrogen in non-small cell lung cancer cells [52] and colon cancer via ERβ [53].

Association of Estrogen Receptor-β Isoforms and Coactivators The coexpression of high AIB-1, NFkB, p-c-Jun, and TIF-2 and ERβ-isoforms was significantly correlatedwith poor clinical prognostic markers, such as high Ki-67, p53, high-grade BCa, large-size BCa, and/or positive LN and with different types of BCa and molecular types. ERβ interacts with the members of the SRC family and other coactivators and coregulate the development and growth of BCa [49–51,54].Such a significant correlation between ERβ isoforms and the coactivators supports the notion that the coactivators are co-implicated in the proliferation of BCa and the risk factors of ERβ-expressing BCa.

In summary, coactivators are significantly and differentially correlated with the expression of ERβ isoforms and clinical parameters and seem to play an important role in directing ERβ-regulating genes or gene sets, further contributing to the functional complexity of ERβ.

 

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