NCOA3

Gene Summary

Gene:NCOA3; nuclear receptor coactivator 3
Aliases: ACTR, AIB1, RAC3, SRC3, pCIP, AIB-1, CTG26, SRC-3, CAGH16, KAT13B, TNRC14, TNRC16, TRAM-1, bHLHe42
Location:20q12
Summary:The protein encoded by this gene is a nuclear receptor coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has histone acetyltransferase activity and recruits p300/CBP-associated factor and CREB binding protein as part of a multisubunit coactivation complex. This protein is initially found in the cytoplasm but is translocated into the nucleus upon phosphorylation. Several transcript variants encoding different isoforms have been found for this gene. In addition, a polymorphic repeat region is found in the C-terminus of the encoded protein. [provided by RefSeq, Mar 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor coactivator 3
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
Show (36)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Translocation
  • Oncogene Proteins
  • Estrogen Receptor alpha
  • Tetrachlorodibenzodioxin
  • p53 Protein
  • Thiazoles
  • Single Nucleotide Polymorphism
  • Cell Proliferation
  • Xenograft Models
  • Two-Hybrid System Techniques
  • Signal Transduction
  • Prostate Cancer
  • siRNA
  • Trinucleotide Repeats
  • Repressor Proteins
  • Transfection
  • Drug Resistance
  • Tamoxifen
  • Nuclear Receptor Coactivator 3
  • Transcriptome
  • Urothelium
  • Acetyltransferases
  • Proto-Oncogene Proteins c-myb
  • Risk Factors
  • Chromosome 20
  • Transcriptional Activation
  • Genetic Predisposition
  • Gene Amplification
  • Estrogen Receptors
  • Tumor Markers
  • Androgen Receptors
  • Survival Rate
  • Transcription
  • Histone Acetyltransferases
  • Up-Regulation
  • Systems Biology
  • Cancer Gene Expression Regulation
  • Trans-Activators
  • Breast Cancer
  • Estradiol
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NCOA3 (cancer-related)

Thewes V, Simon R, Schroeter P, et al.
Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.
Cancer Res. 2015; 75(4):720-31 [PubMed] Related Publications
Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer.

Battistella M, Romero M, Castro-Vega LJ, et al.
The High Expression of the microRNA 17-92 Cluster and its Paralogs, and the Downregulation of the Target Gene PTEN, Is Associated with Primary Cutaneous B-Cell Lymphoma Progression.
J Invest Dermatol. 2015; 135(6):1659-67 [PubMed] Related Publications
The oncogenic microRNA (miR) 17-92 cluster has a causative role in the lymphomagenesis of nodal B-cell lymphomas, by activating proliferation and inhibiting apoptosis. Here we analyzed primary cutaneous B-cell lymphomas for the miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25. In 22 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL-LT) compared with 22 primary cutaneous follicle center lymphomas (PCFCLs), we found that miR-20a and miR-106a were overexpressed. Multivariate Cox analysis showed that higher miR-20a and miR-20b expression levels were associated with shorter disease-free and overall survival, independently from histological type. Gene expression profiling also showed a downregulation of 8 candidate target genes of miR-20a, miR-20b, and miR-106a in PCLBCL-LT compared with PCFCL. Among the candidate target genes, PTEN, NCOA3, and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative reverse transcriptase-PCR on CD20-positive laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with shorter disease-free survival (DFS), independently from the histological type. Altogether, this molecular and bioinformatic study of 44 patient skin biopsy samples showed that the oncogenic miR-17-92 cluster and its paralogs were involved in cutaneous B-cell lymphoma progression, and that the downregulation of the target gene PTEN was associated with shorter DFS.

Ngollo M, Lebert A, Dagdemir A, et al.
The association between histone 3 lysine 27 trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters.
BMC Cancer. 2014; 14:994 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It is well established that genetic and epigenetic alterations are common events in prostate cancer, which may lead to aberrant expression of critical genes. The importance of epigenetic mechanisms in prostate cancer carcinogenesis is increasingly evident. In this study, the focus will be on histone modifications and the primary objectives are to map H3K27me3 marks and quantify RAR beta 2, ER alpha, SRC3, RGMA, PGR, and EZH2 gene expressions in prostate cancer tissues compared to normal tissues. In addition, a data analysis was made in connection with the clinicopathological parameters.
METHODS: 71 normal specimens and 66 cancer prostate tissues were randomly selected in order to assess the proportion of the repressive H3K27me3 mark and gene expression. H3K27me3 level was evaluated by ChIP-qPCR and mRNA expression using RT-qPCR between prostate cancer and normal tissues. Subsequently, western-blotting was performed for protein detection. The analysis of variance (ANOVA) was performed, and Tukey's test was used to correct for multiple comparisons (p-value threshold of 0.05). The principal component analysis (PCA) and discriminant factorial analysis (DFA) were used to explore the association between H3K27me3 level and clinicopathological parameters.
RESULTS: The study demonstrated that H3K27me3 level was significantly enriched at the RAR beta 2, ER alpha, PGR, and RGMA promoter regions in prostate cancer tissues compared to normal tissues. After stratification by clinicopathological parameters, the H3K27me3 level was positively correlated with Gleason score, PSA levels and clinical stages for RAR beta 2, ER alpha, PGR, and RGMA. High H3K27me3 mark was significantly associated with decreased RAR beta 2, ER alpha, PGR and RGMA gene expressions in prostate cancer sample compared to the normal one. Moreover, the results showed that mRNA level of EZH2, AR and SRC3 are upregulated in prostate cancer compared to normal prostate tissues and this correlates positively with Gleason score, PSA levels and clinical stages. Obviously, these observations were confirmed by protein level using western-blot.
CONCLUSIONS: This data clearly demonstrated that H3K27me3 level correlated with aggressive tumor features. Also this study revealed that reverse correlation of RAR beta 2, ER alpha, PGR, and RGMA expressions with EZH2, SRC3, and AR expressions in prostate cancer tissues suggests that these genes are the target of EZH2. Therefore, all therapeutic strategies leading to histone demethylation with epigenetic drugs such as histone methyltransferase inhibitor may be relevant treatments against prostate cancer.

Wargon V, Riggio M, Giulianelli S, et al.
Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.
Int J Cancer. 2015; 136(11):2680-92 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

Geng C, Rajapakshe K, Shah SS, et al.
Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer.
Cancer Res. 2014; 74(19):5631-43 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.

Han G, Xie S, Fang H, et al.
The AIB1 gene polyglutamine repeat length polymorphism contributes to risk of epithelial ovarian cancer risk: a case-control study.
Tumour Biol. 2015; 36(1):371-4 [PubMed] Related Publications
Genes coding for proteins involved in steroid hormone signaling have been identified as ovarian cancer risk-modifier candidates. AIB1 gene (amplified in breast cancer-1), an androgen receptor (AR) coactivator, expresses a polyglutamine (poly-Q) sequence within the carboxyl-terminal coding region. We hypothesized that genotypic variations in the androgen-signaling pathway promote aggressive epithelial ovarian cancer biology and sought to examine the effect of AIB1 poly-Q repeat length on ovarian cancer risk with a case-control study. The genotype analysis of the AIB1 poly-Q repeat was conducted in 3,000 epithelial ovarian cancer (EOC) cases and 3,000 healthy controls. When analyzed as a categorical variable with cutoff of <28 or <29, both of results showed significant asociations. Compared to those with the shorter (<29) AIB1 poly-Q repeat length, women in the category of longer (≥29) poly-Q repeats had a significantly 20 % increased EOC risk (odds ratio (OR) = 1.20; 95 % confidence interval (CI), 1.08-1.33; P = 5.88 × 10(-4)). When analyzed as a continuous covariate, women with longer average poly-Q repeat length had a significantly increased risk of developing EOC (OR = 1.05 for per poly-Q repeat; 95 % CI, 1.00-1.08; P = 0.013). The association was more stronger for per longer allele (OR = 1.07; 95 % CI, 1.01-1.12; P = 0.010). These results strongly suggest that there is a significant effect of AIB1 genetic variation on ovarian cancer risk, and AIB1 underlies the development of ovarian cancer.

Fan P, Agboke FA, Cunliffe HE, et al.
A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer.
Eur J Cancer. 2014; 50(16):2866-76 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: Oestrogen (E2)-stimulated growth re-emerges after a c-Src inhibitor blocking E2-induced apoptosis. A resulting cell line, MCF-7:PF, is selected with features of functional oestrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1Rβ). We addressed the question of whether the selective ER modulator (SERM), 4-hydroxytamoxifen (4-OHT) or other SERMs could target ER to prevent E2-stimulated growth in MCF-7:PF cells.
METHODS: Protein levels of receptors and signalling pathways were examined by immunoblotting. Expression of mRNA was measured through real-time RT-PCR. Recruitment of ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene was detected by chromatin-immunoprecipitation (ChIP).
RESULTS: 4-OHT and other SERMs stimulated cell growth in an ER-dependent manner. However, unlike E2, 4-OHT suppressed classical ER-target genes as does the pure antioestrogen ICI 182,780 (ICI). ChIP assay indicated that 4-OHT did not recruit ER or SRC3 to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1Rβ but increased phosphorylation of IGF-1Rβ. Mechanistic studies revealed that 4-OHT functioned as an agonist to enhance the non-genomic activity of ER and activate focal adhesion molecules to further increase phosphorylation of IGF-1Rβ. Disruption of membrane-associated signalling, IGF-1R and focal adhesion kinase (FAK), completely abolished 4-OHT-stimulated cell growth.
CONCLUSIONS: This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen resistance developed in athymic mice in vivo. Importantly, it provides a rationale that membrane-associated pathways may be valuable therapeutic targets for tamoxifen resistant patients in clinic.

Tan X, Chen M
MYLK and MYL9 expression in non-small cell lung cancer identified by bioinformatics analysis of public expression data.
Tumour Biol. 2014; 35(12):12189-200 [PubMed] Related Publications
Gene expression microarrays are widely used to investigate molecular targets in cancers, including lung cancer. In this study, we analyzed online non-small cell lung cancer (NSCLC) microarray databases, to screen the key genes and pathways related to NSCLC by bioinformatics analyses. And then, the expression levels of two selected genes in the down-regulated co-pathways, myosin light chain kinase (MYLK) and myosin regulatory light chain 9 (MYL9), were determined in tumor, paired paraneoplastic, and normal lung tissues. First, gene set enrichment analysis and meta-analysis were conducted to identify key genes and pathways that contribute to NSCLC carcinogenesis. Second, using the total RNA and protein extracted from lung cancer tissues (n = 240), adjacent non-cancer tissues (n = 240), and normal lung tissues (n = 300), we examined the MYLK and MYL9 expression levels by quantitative real-time PCR and Western blot. Finally, we explored the correlations between mRNA and protein expressions of these two genes and the clinicopathological parameters of NSCLC. Fifteen up-regulated and nine down-regulated co-pathways were observed. A number of differentially expressed genes (CALM1, THBS1, CSF3, BMP2, IL6ST, MYLK, ROCK2, IL3RA, MYL9, PPP2CA, CSF2RB, CNAQ, GRIA2, IL10RA, IL10RB, IL11RA, LIFR, PLCB4, and RAC3) were identified (P < 0.01) in the down-regulated co-pathways. The expression levels of MYLK and MYL9, which act downstream of the vascular smooth muscle contraction signal pathway and focal adhesion pathway, were significantly lower in cancer tissue than those in the paraneoplastic and normal tissues (P < 0.05). Moreover, the expression levels of these two genes in stages III and IV NSCLC were significantly increased, when compared to stages I and II, and expressions levels in NSCLC with lymphatic metastasis were higher than that without lymphatic metastasis (P < 0.05). Additionally, significant lower expression levels of the two genes were found in smokers than in nonsmokers (P < 0.05). In contrast, gender, differentiated degrees, and pathohistological type appeared to have no impact on these gene expressions (P > 0.05). These findings suggested that low MYLK and MYL9 expressions might be associated with the development of NSCLC. These genes may be also relevant to NSCLC metastasis. Future investigations with large sample sizes needed to verify these findings.

Pedersen AM, Thrane S, Lykkesfeldt AE, Yde CW
Sorafenib and nilotinib resensitize tamoxifen resistant breast cancer cells to tamoxifen treatment via estrogen receptor α.
Int J Oncol. 2014; 45(5):2167-75 [PubMed] Related Publications
Tamoxifen‑resistant breast cancer is a major clinical problem and new treatment strategies are highly warranted. In this study, the multitargeting kinase inhibitors sorafenib and nilotinib were investigated as potential new treatment options for tamoxifen‑resistant breast cancer. The two compounds inhibited cell growth, reduced expression of total estrogen receptor α (ER), Ser118-phosphorylated ER, FOXA1 and AIB1 and resensitized tamoxifen‑resistant cells to tamoxifen. The ER downmodulator fulvestrant exerted strong growth inhibition of tamoxifen‑resistant cells and addition of sorafenib and nilotinib could not further suppress growth, showing that sorafenib and nilotinib exerted growth inhibition via ER. In support of this, estradiol prevented sorafenib and nilotinib mediated growth inhibition. These results demonstrate that sorafenib and nilotinib act via ER and ER-associated proteins, indicating that these kinase inhibitors in combination with tamoxifen may be potential new treatments for tamoxifen‑resistant breast cancer.

Ciarmela P, Carrarelli P, Islam MS, et al.
Ulipristal acetate modulates the expression and functions of activin a in leiomyoma cells.
Reprod Sci. 2014; 21(9):1120-5 [PubMed] Related Publications
Uterine leiomyoma is the most common benign gynecological tumor in women of reproductive age and represents the single most common indication for hysterectomy. A development of new treatments is necessary for a medical management, and in this direction, several hormonal drugs are under investigation. Ulipristal acetate (UPA; a selective progesterone receptor modulator) is considered as one of the most promising because progesterone has a critical role in development and growth of uterine leiomyoma. The effect of steroids is partly mediated by growth factors like activin A which increases extracellular matrix expression contributing to the growth of leiomyoma. The present study aimed to test whether UPA acts on leiomyoma cells affecting expression and functions of activin A system. Cultured myometrial and leiomyoma cells were treated with UPA, and messenger RNA (mRNA) expression levels of activin A (inhibin βA [INHBA] subunits), its binding proteins (follistatin [FST] and FST-related gene), and its receptors (activin receptor-like kinase 4 [ALK4], activin receptor type [ActR] II, and ActRIIB) were evaluated. The effect of UPA on activin A modulation of fibronectin and vascular endothelial growth factor A (VEGF-A) mRNA expression in cultured myometrial and leiomyoma cells was also studied. Ulipristal acetate decreased INHBA, FST, ActRIIB, and Alk4 mRNA expressions in leiomyoma cultured cells. In addition, UPA was able to block the activin A-induced increase in fibronectin or VEGF-A mRNA expression in myometrial and in leiomyoma cultured cells. The present data show that UPA inhibits activin A expression and functions in leiomyoma cells, and this may represent a possible mechanism of action of the drug on uterine leiomyoma.

Chen L, Zhang Z, Qiu J, et al.
Chaperonin CCT-mediated AIB1 folding promotes the growth of ERα-positive breast cancer cells on hard substrates.
PLoS One. 2014; 9(5):e96085 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Clinical observations have revealed a strong association between estrogen receptor alpha (ERα)-positive tumors and the development of bone metastases, however, the mechanism underlying this association remains unknown. We cultured MCF-7 (ERα-positive) on different rigidity substrates. Compared with cells grown on more rigid substrates (100 kPa), cells grown on soft substrates (10 kPa) exhibited reduced spreading ability, a lower ratio of cells in the S and G2/M cell cycle phases, and a decreased proliferation rate. Using stable isotope labeling by amino acids (SILAC), we further compared the whole proteome of MCF-7 cells grown on substrates of different rigidity (10 and 100 kPa), and found that the expression of eight members of chaperonin CCT increased by at least 2-fold in the harder substrate. CCT folding activity was increased in the hard substrate compared with the soft substrates. Amplified in breast cancer 1 (AIB1), was identified in CCT immunoprecipitates. CCT folding ability of AIB1 increased on 100-kPa substrate compared with 10- and 30-kPa substrates. Moreover, using mammalian two-hybrid protein-protein interaction assays, we found that the polyglutamine repeat sequence of the AIB1 protein was essential for interaction between CCTζ and AIB1. CCTζ-mediated AIB1 folding affects the cell area spreading, growth rate, and cell cycle. The expressions of the c-myc, cyclin D1, and PgR genes were higher on hard substrates than on soft substrate in both MCF-7 and T47D cells. ERα and AIB1 could up-regulate the mRNA and protein expression levels of the c-myc, cyclin D1, and PgR genes, and that 17 β-estradiol could enhance this effects. Conversely, 4-hydroxytamoxifen, could inhibit these effects. Taken together, our studies demonstrate that some ERα-positive breast cancer cells preferentially grow on more rigid substrates. CCT-mediated AIB1 folding appears to be involved in the rigidity response of breast cancer cells, which provides novel insight into the mechanisms of bone metastasis.

Olar A, He D, Florentin D, et al.
Biologic correlates and significance of axonogenesis in prostate cancer.
Hum Pathol. 2014; 45(7):1358-64 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Cancer-related axonogenesis and neurogenesis are recently described biologic phenomena. Our previously published data showed that nerve density and the number of neurons in the parasympathetic ganglia are increased in prostate cancer (PCa) and associated with aggressive disease. Tissue microarrays were constructed from 640 radical prostatectomy specimens with PCa. Anti-protein gene product 9.5 (PGP 9.5) antibodies were used to identify and quantify nerve density. Protein expression was objectively analyzed using deconvolution imaging, image segmentation, and image analysis. Data were correlated with clinicopathological variables and tissue biomarkers available in our database. Nerve density, as measured by PGP 9.5 expression, had a weak but significant positive correlation with the lymph node status (ρ = 0.106; P = .0275). By Cox univariate analysis, PGP 9.5 was a predictor of time to biochemical recurrence, but not on multivariate analysis. Increased nerve density correlated with increased proliferation of PCa cells. It also correlated with expression of proteins involved in survival pathways (Phosphorylated alpha serine/threonine-protein kinase, NFκB, GSK-2, PIM-2, c-Myc, SKP-2, SRF, P27n, PTEN), with increased levels of hormonal regulation elements (androgen receptor, estrogen receptor α), and coregulators and repressors (SRC-1, SRC-2, AIB-1, DAX). Axonogenesis is a recently described phenomenon of paramount importance in the biology of PCa. Although the degree of axonogenesis is predictive of aggressive behavior in PCa, it does not add to the information present in current models on multivariate analysis. We present data that corroborate that axonogenesis is involved in biologic processes such as proliferation of PCa, through activation of survival pathways and interaction with hormonal regulation.

Yan F, Yu Y, Chow DC, et al.
Identification of verrucarin a as a potent and selective steroid receptor coactivator-3 small molecule inhibitor.
PLoS One. 2014; 9(4):e95243 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Members of the steroid receptor coactivator (SRC) family are overexpressed in numerous types of cancers. In particular, steroid receptor coactivator 3 (SRC-3) has been recognized as a critical coactivator associated with tumor initiation, progression, recurrence, metastasis, and chemoresistance where it interacts with multiple nuclear receptors and other transcription factors to enhance their transcriptional activities and facilitate cross-talk between pathways that stimulate cancer progression. Because of its central role as an integrator of growth signaling pathways, development of small molecule inhibitors (SMIs) against SRCs have the potential to simultaneously disrupt multiple signal transduction networks and transcription factors involved in tumor progression. Here, high-throughput screening was performed to identify compounds able to inhibit the intrinsic transcriptional activities of the three members of the SRC family. Verrucarin A was identified as a SMI that can selectively promote the degradation of the SRC-3 protein, while affecting SRC-1 and SRC-2 to a lesser extent and having no impact on CARM-1 and p300 protein levels. Verrucarin A was cytotoxic toward multiple types of cancer cells at low nanomolar concentrations, but not toward normal liver cells. Moreover, verrucarin A was able to inhibit expression of the SRC-3 target genes MMP2 and MMP13 and attenuated cancer cell migration. We found that verrucarin A effectively sensitized cancer cells to treatment with other anti-cancer drugs. Binding studies revealed that verrucarin A does not bind directly to SRC-3, suggesting that it inhibits SRC-3 through its interaction with an upstream effector. In conclusion, unlike other SRC SMIs characterized by our laboratory that directly bind to SRCs, verrucarin A is a potent and selective SMI that blocks SRC-3 function through an indirect mechanism.

Jiang HL, Yu H, Ma X, et al.
MicroRNA-195 regulates steroid receptor coactivator-3 protein expression in hepatocellular carcinoma cells.
Tumour Biol. 2014; 35(7):6955-60 [PubMed] Related Publications
Multiple studies have shown that steroid receptor coactivator-3 (SRC-3) is upregulated and promotes cell proliferation in several human cancers, including breast, lung, and prostate carcinoma. However, its molecular determinants remain largely unexplored. In the current study, by way of informatics software, we found that MicroRNA-195 (miR-195) could negatively regulate protein levels of SRC-3 through targeting its 3'-untranslated region (3'-UTR) in hepatocellular carcinoma (HCC) cells. As a result, miR-195 mimics inhibited while its antisense enhanced SRC-3 protein levels. Furthermore, miR-195 could modulate cell proliferation and tumor growth in vivo and in vitro. Therefore, our results demonstrate a novel molecular mechanism for the dysregulated expression of SRC-3 in hepatocellular carcinoma.

Dong S, Zhao J, Wei J, et al.
F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation.
Mol Cancer. 2014; 13:76 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.
METHODS: FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining.
RESULTS: Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype.
CONCLUSIONS: Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis.

Garee JP, Chien CD, Li JV, et al.
Regulation of HER2 oncogene transcription by a multifunctional coactivator/corepressor complex.
Mol Endocrinol. 2014; 28(6):846-59 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Transcription of the HER2 oncogene can be repressed by estrogen (E2). We now show that, a splice isoform of the nuclear receptor coactivator AIB1, AIB1-Δ4, is able to reverse E2 repression of HER2 gene expression in breast cancer cells. The first 224 amino acids of AIB1 that are absent in AIB1-Δ4, bind a co-repressor, ANCO1. Using chromatin immunoprecipitation assay approaches in MCF7 and BT474 cell lines, we demonstrate that AIB1 and AIB1-Δ4 can bind to the E2 regulatory site in the first intron of the HER2 gene, after E2 treatment, but only full-length AIB1 recruits ANCO1. Consistent with E2-induced chromatin repression, the AIB1-ANCO1 complex recruits HDAC3 and HDAC4 to the intronic estrogen response element and the proximal promoter acquires the repressive chromatin mark H3K9me3 and loses H3K4me1. In contrast, AIB1-Δ4 does not recruit ANCO 1, HDAC3, or HDAC4 and the proximal promoter retains activation marks of H3K4me1. In cell lines with low levels of ANCO1 (T47D), E2 does not repress HER2 gene transcription but the repressive response can be restored by overexpression of ANCO1. ANCO1 can also repress other E2-responsive genes, indicating that AIB1, AIB1-Δ4 and ANCO1 are important determinants of endocrine and growth factor responsiveness in breast cancer.

Zhao W, Chang C, Cui Y, et al.
Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible factor 1α.
J Biol Chem. 2014; 289(16):11219-29 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as "Warburg effect," to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

Tabarestani S, Ghaderian SM, Rezvani H, Mirfakhraie R
Expression profiling of breast cancer patients treated with tamoxifen: prognostic or predictive significance.
Med Oncol. 2014; 31(4):896 [PubMed] Related Publications
Approximately 70% of breast cancers are estrogen receptor (ER) positive, and interfering with estrogen action with tamoxifen has been the treatment of choice for ER-positive breast cancer patients. However, about a third of patients treated with tamoxifen will experience a recurrence of cancer. The expression analysis of selected genes involved in tamoxifen/estrogen and receptor tyrosine kinase signaling pathways can help to further decipher mechanisms of recurrence in ER+ tumors and contribute to the development of prognostic and possibly predictive biomarkers. We selected seven genes (ESR1, CCND1, MYC, HER2, AKT1, AIB1 and NCOR1), which are components of these pathways. A case-control study was designed. All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced an early recurrence of cancer while receiving tamoxifen treatment. Expression levels of selected genes in both groups were compared. Expression levels of CCND1 (p < 0.001), HER2 (p < 0.001), AKT1 (p = 0.038) and AIB1 (p = 0.004) were significantly higher in recurrent tumors compared to non-recurrent tumors, while expression levels of NCOR1 (p < 0.001) were significantly lower in recurrent tumors. In multivariable analysis, CCND1 (p < 0.001), HER2 (p = 0.003), AIB1 (p = 0.036) and NCOR1 (p = 0.002) remained significant predictors of recurrence. Expression levels of CCND1, HER2, AIB1 and NCOR1 were detected as independent predictors of recurrence in this cohort of tamoxifen-treated patients. Further work should be done to validate the predictive value of this gene profile for tamoxifen response.

Dabydeen SA, Furth PA
Genetically engineered ERα-positive breast cancer mouse models.
Endocr Relat Cancer. 2014; 21(3):R195-208 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The majority of human breast cancers are estrogen receptor-positive (ER+), but this has proven challenging to model in genetically engineered mice. This review summarizes information on 21 mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent. ESR1, CCDN1, prolactin, TGFα, AIB1, ESPL1, and WNT1 overexpression, PIK3CA gain of function, as well as loss of P53 (Trp53) or STAT1 are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse with Brca1 and p53 deficiency and 7,12-dimethylbenz(a)anthracene exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from 3 to 26 months and the percentage of cancers that are ER+ vary from 21 to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1, and NIH nude. Most models have only been studied on one strain background. In summary, while a range of models are available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization, and opportunity for development of new models remains.

Wagner M, Koslowski M, Paret C, et al.
NCOA3 is a selective co-activator of estrogen receptor α-mediated transactivation of PLAC1 in MCF-7 breast cancer cells.
BMC Cancer. 2013; 13:570 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The placenta-specific 1 (PLAC1) gene encodes a membrane-associated protein which is selectively expressed in the placental syncytiotrophoblast and in murine fetal tissues during embryonic development. In contrast to its transcriptional repression in all other adult normal tissues, PLAC1 is frequently activated and highly expressed in a variety of human cancers, in particular breast cancer, where it associates with estrogen receptor α (ERα) positivity. In a previous study, we showed that ERα-signaling in breast cancer cells transactivates PLAC1 expression in a non-classical pathway. As the members of the p160/nuclear receptor co-activator (NCOA) family, NCOA1, NCOA2 and NCOA3 are known to be overexpressed in breast cancer and essentially involved in estrogen-mediated cancer cell proliferation we asked if these proteins are involved in the ERα-mediated transactivation of PLAC1 in breast cancer cells.
METHODS: Applying quantitative real-time RT-PCR (qRT-PCR), Western Blot analysis and chromatin immunoprecipitation, we analyzed the involvement of NCOA1, NCOA2, NCOA3 in the ERα-mediated transactivation of PLAC1 in the breast cancer cell lines MCF-7 and SK-BR-3. RNAi-mediated silencing of NCOA3, qRT-PCR, Western blot analysis and ERα activation assays were used to examine the role of NCOA3 in the ERα-mediated regulation of PLAC1 in further detail. Transcript expression of NCOA3 and PLAC1 in 48 human breast cancer samples was examined by qRT-PCR and statistical analysis was performed using Student's t-test.
RESULTS: We detected selective recruitment of NCOA3 but not NCOA1 or NCOA2 to the PLAC1 promoter only in ERα-positive MCF-7 cells but not in ERα-negative SK-BR-3 breast cancer cells. In addition, we demonstrate that silencing of NCOA3 results in a remarkable decrease of PLAC1 expression levels in MCF-7 cells which cannot be restored by treatment with estradiol (E₂). Moreover, significant higher transcript levels of PLAC1 were found only in ERα-positive human breast cancer samples which also show a NCOA3 overexpression.
CONCLUSIONS: In this study, we identified NCOA3 as a selective co-activator of ERα-mediated transactivation of PLAC1 in MCF-7 breast cancer cells. Our data introduce PLAC1 as novel target gene of NCOA3 in breast cancer, supporting the important role of both factors in breast cancer biology.

Wang Y, Ren F, Wang Y, et al.
CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer.
Carcinogenesis. 2014; 35(5):983-91 [PubMed] Related Publications
The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1α, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.

Geng S, Wang X, Xu X, et al.
Steroid receptor co-activator-3 promotes osteosarcoma progression through up-regulation of FoxM1.
Tumour Biol. 2014; 35(4):3087-94 [PubMed] Related Publications
Increasing evidence suggests that the three homologous members of steroid receptor co-activator (SRC) family (SRC-1, SRC-2, and SRC-3) play key roles in enhancing cell proliferation in various human cancers, such as breast, prostate, and hepatocellular carcinoma. However, the function of SRC-3 in osteosarcoma remains largely unexplored. In the current study, we found that SRC-3, but not SRC-1 and SRC-2, was dramatically up-regulated in human osteosarcoma tissues, compared with adjacent normal tissues. To explore the functions of SRC-3 in osteosarcoma, in vitro studies were performed in MG63 and U2OS cells. SRC-3 overexpression promoted osteosarcoma cell proliferation, whereas knockdown of SRC-3 inhibits its proliferation. In support of these findings, we further demonstrated that SRC-3 up-regulated FoxM1 expression through co-activation of C/EBPγ. Together our results show that SRC-3 drives osteosarcoma progression and imply it as a therapeutic target to abrogate osteosarcoma.

Gojis O, Kubecova M, Rosina J, et al.
Expression of selected proteins in breast cancer brain metastases.
Folia Histochem Cytobiol. 2013; 51(3):213-8 [PubMed] Related Publications
The aim of the study was to assess the immunohistochemical (IHC) profiles of SRC3, Pax2, ER, PgR, Her2, EGFR, CK5/6, and Ki67 proteins in breast-cancer brain metastasis. The study utilized tumor samples from 30 metastatic patients and calculated correlations between all IHC variables. In fourteen cases, primary breast cancers paired with secondary deposits were analyzed. We evaluated the association between IHC status in the primary and secondary deposits, grade, and histotype of the tumors. The examination of the metastatic deposits in all 30 patients resulted in positive detection in the following cases: SRC3 in 20 cases (66.6%), Pax2 in 22 (73.3%), ER in 22 (73.3%), PgR in 25 (83.3%), Her2 in 10 (33.3%), EGFR in 12 (40%), CK5/6 in 7 (23.3%), and Ki67 in 23 (76.6%). Grade 2 was found in 13.3% of all patients, and grade 3 in 86.7%. SRC3 and Pax2 were positive in both G2 and G3. Invasive lobular carcinoma and invasive ductal carcinoma were diagnosed in 23.3% and 76.7% of cases, respectively. There were no differences between the IHC expression of the studied proteins in either grading or histotype of the tumors. In the IHC profiles, which included SRC3, Pax2, ER, PgR, Her2, CK5/6, Ki67, and EGFR, we found no statistically significant differences between the primary cancer and the brain metastasis. In our study of metastatic breast carcinoma deposits, there was no correlation between SRC3, Pax2 status and histotype, and tumor grade. The IHC status of the paired primary and metastatic deposits did not differ in a statistically significant manner.

Fenne IS, Helland T, Flågeng MH, et al.
Downregulation of steroid receptor coactivator-2 modulates estrogen-responsive genes and stimulates proliferation of mcf-7 breast cancer cells.
PLoS One. 2013; 8(7):e70096 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERα) activity. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERα and changed expression of the ERα target gene, pS2. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells.

Zhang Y, Wang JH, Liu B, Qu PB
Steroid receptor coactivator-3 promotes bladder cancer through upregulation of CXCR4.
Asian Pac J Cancer Prev. 2013; 14(6):3847-50 [PubMed] Related Publications
The three homologous members of the p160 SRC family (SRC-1, SRC-2 and SRC-3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all the transcriptional co-activators. Recent work has indicated that the SRC-3 gene is subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRC-3 promotes breast and prostate cancer cell proliferation and survival, have been identified. However, the function of SRC-3 in bladder cancer remains poorly understood. In the present study, our results indicate that overexpression of SRC-3 promotes bladder cancer cell proliferation whereas knockdown of SRC-3 results in inhibition. At the molecular level, we further established that CXCR4 is a transcriptional target of SRC-3. Therefore, our study first identified that SRC-3 plays a critical role in the bladder cancer, which may be a target beneficial for its prevention and treatment.

Turkel N, Sahota VK, Bolden JE, et al.
The BTB-zinc finger transcription factor abrupt acts as an epithelial oncogene in Drosophila melanogaster through maintaining a progenitor-like cell state.
PLoS Genet. 2013; 9(7):e1003627 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled (scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state.

Ory V, Tassi E, Cavalli LR, et al.
The nuclear coactivator amplified in breast cancer 1 maintains tumor-initiating cells during development of ductal carcinoma in situ.
Oncogene. 2014; 33(23):3033-42 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The key molecular events required for the formation of ductal carcinoma in situ (DCIS) and its progression to invasive breast carcinoma have not been defined. Here, we show that the nuclear receptor coactivator amplified in breast cancer 1 (AIB1) is expressed at low levels in normal breast but is highly expressed in DCIS lesions. This is of significance since reduction of AIB1 in human MCFDCIS cells restored a more normal three-dimensional mammary acinar structure. Reduction of AIB1 in MCFDCIS cells, both before DCIS development or in existing MCFDCIS lesions in vivo, inhibited tumor growth and led to smaller, necrotic lesions. AIB1 reduction in MCFDCIS cells was correlated with significant reduction in the CD24-/CD44+ breast cancer-initiating cell (BCIC) population, and a decrease in myoepithelial progenitor cells in the DCIS lesions in vitro and in vivo. The loss of AIB1 in MCFDCIS cells was also accompanied by a loss of expression of NOTCH 2, 3 and 4, JAG2, HES1, GATA3, human epidermal growth factor receptor 2 (HER2) and HER3 in vivo. These signaling molecules have been associated with differentiation of breast epithelial progenitor cells. These data indicate that AIB1 has a central role in the initiation and maintenance of DCIS and that reduction of AIB1 causes loss of BCIC, loss of components of the NOTCH, HER2 and HER3 signaling pathways and fewer DCIS myoepithelial progenitor cells in vivo. We propose that increased expression of AIB1, through the maintenance of BCIC, facilitates formation of DCIS, a necessary step before development of invasive disease.

Foulds CE, Feng Q, Ding C, et al.
Proteomic analysis of coregulators bound to ERα on DNA and nucleosomes reveals coregulator dynamics.
Mol Cell. 2013; 51(2):185-99 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Chromatin immunoprecipitation studies have mapped protein occupancies at many genomic loci. However, a detailed picture of the complexity of coregulators (CoRs) bound to a defined enhancer along with a transcription factor is missing. To address this, we used biotin-DNA pull-down assays coupled with mass spectrometry-immunoblotting to identify at least 17 CoRs from nuclear extracts bound to 17β-estradiol (E2)-liganded estrogen receptor-α on estrogen response elements (EREs). Unexpectedly, these complexes initially are biochemically stable and contain certain atypical corepressors. Addition of ATP dynamically converts these complexes to an "activated" state by phosphorylation events, primarily mediated by DNA-dependent protein kinase. Importantly, a "natural" ERE-containing enhancer and nucleosomal EREs recruit similar complexes. We further discovered the mechanism whereby H3K4me3 stimulates ERα-mediated transcription as compared with unmodified nucleosomes. H3K4me3 templates promote specific CoR dynamics in the presence of ATP and AcCoA, as manifested by CBP/p300 and SRC-3 dismissal and SAGA and TFIID stabilization/recruitment.

Madak-Erdogan Z, Charn TH, Jiang Y, et al.
Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.
Mol Syst Biol. 2013; 9:676 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The closely related transcription factors (TFs), estrogen receptors ERα and ERβ, regulate divergent gene expression programs and proliferative outcomes in breast cancer. Utilizing breast cancer cells with ERα, ERβ, or both receptors as a model system to define the basis for differing response specification by related TFs, we show that these TFs and their key coregulators, SRC3 and RIP140, generate overlapping as well as unique chromatin-binding and transcription-regulating modules. Cistrome and transcriptome analyses and the use of clustering algorithms delineated 11 clusters representing different chromatin-bound receptor and coregulator assemblies that could be functionally associated through enrichment analysis with distinct patterns of gene regulation and preferential coregulator usage, RIP140 with ERβ and SRC3 with ERα. The receptors modified each other's transcriptional effect, and ERβ countered the proliferative drive of ERα through several novel mechanisms associated with specific binding-site clusters. Our findings delineate distinct TF-coregulator assemblies that function as control nodes, specifying precise patterns of gene regulation, proliferation, and metabolism, as exemplified by two of the most important nuclear hormone receptors in human breast cancer.

Wang M, Zhao F, Li S, et al.
AIB1 cooperates with ERα to promote epithelial mesenchymal transition in breast cancer through SNAI1 activation.
PLoS One. 2013; 8(6):e65556 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Epithelial Mesenchymal Transition (EMT) plays a major role in cancer metastasis. Several genes have been shown to play a role in EMT, and one of these is Amplified-in-breast cancer 1 (AIB1), which has oncogenic function and is known to be amplified in breast cancer. However, the role of AIB1 in EMT remains largely undefined at the molecular level. In this study, the effect of AIB1 overexpression on the EMT of the breast cancer cell line T47D was investigated. Overexpression of AIB1 disrupted the epithelial morphology of the cells. At the same time, the cells displayed a strong metastasis and reduced level of the epithelial marker E-cadherin. In contrast, knockdown of AIB1 in T47D cells increased cell-cell adhesion and produced weak metastasis, as well as a higher level of E-cadherin expression. We proposed that the regulation of EMT by AIB1 occurred through the action of the transcription factor SNAI1, and demonstrated that such interaction required the participation of ERα and the presence of ERα-binding site on SNAI1 promoter. The expression level of E-cadherin and the extent of cell migration and invasion in SNAI1-knocked down T47D cells that overexpressed AIB1 were similar to those of T47D cells that did not overexpress AIB1 and had no SNAI1 knockdown. Taken together, these results suggested that AIB1 exerted its effect on EMT through its interaction with ERα, which could directly bind to the ERα-binding site on the SNAI1 promoter, allowing the AIB1-ERα complex to promote the transcription of SNAI1 and eventually led to repression of E-cadherin expression, consistent with the loss of E-cadherin being a hallmark of EMT.

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