NCOA4

Gene Summary

Gene:NCOA4; nuclear receptor coactivator 4
Aliases: RFG, ELE1, PTC3, ARA70
Location:10q11.2
Summary:This gene encodes an androgen receptor coactivator. The encoded protein interacts with the androgen receptor in a ligand-dependent manner to enhance its transcriptional activity. Chromosomal translocations between this gene and the ret tyrosine kinase gene, also located on chromosome 10, have been associated with papillary thyroid carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes are present on chromosomes 4, 5, 10, and 14. [provided by RefSeq, Feb 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor coactivator 4
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 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.

  • Tyrphostins
  • Cancer DNA
  • Base Sequence
  • Radiation-Induced Cancer
  • FISH
  • Nuclear Receptor Coactivators
  • Radioactive Hazard Release
  • Trans-Activators
  • Adolescents
  • Cancer Gene Expression Regulation
  • Androgen Receptors
  • Childhood Cancer
  • Oncogene Fusion Proteins
  • p300-CBP Transcription Factors
  • Drosophila Proteins
  • Translocation
  • Gene Expression Profiling
  • Oncogene Proteins
  • Immunohistochemistry
  • Papillary Carcinoma
  • Histone Acetyltransferases
  • Transfection
  • Genetic Predisposition
  • Messenger RNA
  • RTPCR
  • Prostate Cancer
  • Proto-Oncogene Proteins c-ret
  • Thyroid Cancer
  • Molecular Sequence Data
  • Single Nucleotide Polymorphism
  • NCOA4
  • Neoplastic Cell Transformation
  • Polymerase Chain Reaction
  • Gene Rearrangement
  • Oncogenes
  • Chromosome 10
  • Receptor Protein-Tyrosine Kinases
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Intracellular Signaling Peptides and Proteins
Tag cloud generated 27 February, 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.

Entity Topic PubMed Papers
Thyroid CancerRET-PTC3 (RET-ELE1) Rearangements in Papillary Thyroid Cancer
The RET gene is frequently involved in structural rearrangements with either PCT1 (CCDC6) or PCT3 (NCOA4), resulting in chimeric fusion proteins which are characteristic of Papillary Thyroid Cancer. Detection of this may aid differential diagnosis of papillary vs. follicular thyroid cancer.
View Publications148
Prostate CancerNCOA4 and Prostate Cancer View Publications19

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

Latest Publications: NCOA4 (cancer-related)

Malaguarnera R, Chen KY, Kim TY, et al.
Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines.
J Clin Endocrinol Metab. 2014; 99(10):E1976-87 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
CONTEXT: Thyroid growth is regulated by TSH and requires mammalian target of rapamycin (mTOR). Thyroid cancers frequently exhibit mutations in MAPK and/or phosphoinositol-3-kinase-related kinase effectors.
OBJECTIVE: The objective of the study was to explore the contribution of RET/PTC, RAS, and BRAF to mTOR regulation and response to mTOR inhibitors.
METHODS: PCCL3 cells conditionally expressing RET/PTC3, HRAS(G12V), or BRAF(V600E) and human thyroid cancer cells harboring mutations of these genes were used to test pathways controlling mTOR and its requirement for growth.
RESULTS: TSH/cAMP-induced growth of PCCL3 cells requires mTOR, which is stimulated via protein kinase A in a MAPK kinase (MEK)- and AKT-independent manner. Expression of RET/PTC3, HRAS(G12V), or BRAF(V600E) in PCCL3 cells induces mTOR but does not entirely abrogate the cAMP-mediated control of its activity. Acute oncoprotein-induced mTOR activity is regulated by MEK and AKT, albeit to differing degrees. By contrast, mTOR was not activated by TSH/cAMP in human thyroid cancer cells. Tumor genotype did not predict the effects of rapamycin or the mTOR kinase inhibitor AZD8055 on growth, with the exception of a PTEN-null cell line. Selective blockade of MEK did not influence mTOR activity of BRAF or RAS mutant cells. Combined MEK and mTOR kinase inhibition was synergistic on growth of BRAF- and RAS-mutant thyroid cancer cells in vitro and in vivo.
CONCLUSION: Thyroid cancer cells lose TSH/cAMP dependency of mTOR signaling and cell growth. mTOR activity is not decreased by the MEK or AKT inhibitors in the RAS or BRAF human thyroid cancer cell lines. This may account for the augmented effects of combining the mTOR inhibitors with selective antagonists of these oncogenic drivers.

Rao PJ, Vardhini NV, Parvathi MV, et al.
Prevalence of RET/PTC1 and RET/PTC3 gene rearrangements in Chennai population and its correlation with clinical parameters.
Tumour Biol. 2014; 35(10):9539-48 [PubMed] Related Publications
Thyroid cancer is one of the most common endocrine disorders in the world. In India, about 42 million people suffer from various thyroid disorders. However, based on population-based cancer registry (PBCR) and Chennai cancer registry, thyroid cancer is emerging as a common cancer particularly in Chennai. Papillary thyroid carcinoma is considered as the most prevalent cancer constituting about 80-85 % of thyroid malignancies. Rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are one of the major genetic alterations found in papillary thyroid carcinoma. This present study aims at estimating the frequency of RET/PTC1 and RET/PTC3 gene rearrangements in Chennai population and investigating the correlation between RET/PTC gene expressions with clinical parameters. Formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from 30 patients with papillary thyroid carcinoma were analyzed. Initially, to differentiate classic and follicular variants of papillary thyroid carcinoma samples, immunohistochemistry was performed. Thereafter, total RNA was isolated, and quantitative evaluation of RET/PTC1 and RET/PTC3 gene rearrangements by real-time PCR was performed. Chi-square test was performed to understand the correlation between positive and negative mutations of RET/PTC messenger RNA (mRNA) expression with clinical parameters. RET/PTC3 gene rearrangements were identified in 26/30 (86.67 %) cases, and none of the patient in our series had RET/PTC1 gene rearrangements. There was no statistically significant difference observed between positive and negative mutations of RET/PTC3 mRNA expression with clinic pathological parameters. Our results indicate that RET/PTC3 gene rearrangements are the most prevalent form of rearrangements in PTCs of Chennai population.

Dacic S, Luvison A, Evdokimova V, et al.
RET rearrangements in lung adenocarcinoma and radiation.
J Thorac Oncol. 2014; 9(1):118-20 [PubMed] Related Publications
BACKGROUND: RET rearrangement, a hallmark of radiation-induced thyroid cancer, has been reported to occur in 1% of lung adenocarcinoma patients. Patients with this rearrangement tend to be younger and never smokers, raising a possibility of other causes, such as radiation. We hypothesized that RET chromosomal rearrangement may represent a genetic mechanism of radiation-induced lung cancer.
METHODS: Two hundred forty-five consecutive primary lung adenocarcinomas without history of radiation and 38 lung adenocarcinoma patients with a history of therapeutic radiation for breast carcinoma or mediastinal Hodkgin lymphoma were tested for RET rearrangement by fluorescence in situ hybridization. Human lung adenocarcinoma cells (201T) were subjected to γ radiation and tested for RET gene fusions by reverse transcriptase-polymerase chain reaction and Southern blot hybridization.
RESULTS: We identified one case with RET rearrangement in the group without history of radiation (1 of 240; 0.4%) and two cases in the group with history of radiation (2 of 37; 5.4%; P=0.0436). Both these patients were women, who were former smokers with a history of breast carcinoma treated with surgery and radiation. Furthermore, we found that RET fusions could be directly induced in 201T human lung cells by exposure to 1 Gy of γ radiation. All fusions identified were between RET and KIF5B genes, and no RET fusions to CCDC6 or NCOA4 genes, characteristic for thyroid cancer, were identified in the irradiated lung cells.
CONCLUSION: RET fusions may represent a genetic mechanism of radiation-induced lung adenocarcinoma.

Shang Z, Niu Y, Cai Q, et al.
Human kallikrein 2 (KLK2) promotes prostate cancer cell growth via function as a modulator to promote the ARA70-enhanced androgen receptor transactivation.
Tumour Biol. 2014; 35(3):1881-90 [PubMed] Related Publications
Recent data suggested that tissue human kallikrein 2 (KLK2) might be involved in the carcinogenesis and tumor metastasis of prostate cancer (PCa). However, the detailed pathophysiological roles of KLK2 in PCa remain unclear. We report here that KLK2 may be treated as a potential therapeutic target in castration-resistant PCa (CRPC). Histologic analyses show that the increased KLK2 expression is correlated with higher cell proliferation rate and lower cell apoptosis index in CRPC specimens. Adding functional KLK2 cDNA into high passage LNCaP cells led to increased cell growth, and knockdown of KLK2 expression with KLK2-siRNA in LNCaP cells resulted in increased cell apoptosis with cell growth arrest at the G1 phase. Results from in vitro colony formation assay and in vivo xenografted PCa tissues also demonstrated that targeting KLK2 led to suppressed growth of PCa in the castration-resistant stage. Further mechanism dissection shows that KLK2 may cooperate with the AR coregulator, ARA70, to enhance AR transactivation that may result in alteration of PCa formation. Together, these results suggested KLK2 might become a new therapeutic target to battle the CRPC and KLK2-siRNA may be developed as an alternative approach to suppress PCa growth.

Proietti A, Sartori C, Borrelli N, et al.
Follicular-derived neoplasms: morphometric and genetic differences.
J Endocrinol Invest. 2013; 36(11):1055-61 [PubMed] Related Publications
BACKGROUND: The distinction between follicular adenomas (FAs) and well differentiated follicular and papillary carcinomas is often a demanding task and sometimes only intuitive.
AIM: We report an histomorphological evaluation of follicular neoplasms [FAs, follicular carcinomas (FCs), and follicular variant of papillary carcinomas (FVPTCs)], supported by a qualitative and quantitative image analysis and by a molecular characterization.
MATERIAL AND METHODS: Tumor fibrosis and haemorrhage, neoplastic capsule thickness, follicle diameter, number of neoplastic cells, nuclear diameter of neoplastic cells, vessels density, vessels area and intratumoral distribution were evaluated. Ras and BRAF mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements were analyzed. Correlations with clinico-pathological features have been studied.
RESULTS: We found that FAs had a more extensive intratumoral haemorrhage, while malignant neoplasms were characterized by an evident fibrosis, higher cellularity and larger size. FVPTCs had higher nuclear diameter; cells count was higher in the minimally invasive follicular thyroid carcinomas, as well as a thickener neoplastic capsule. The CD34 stain showed a higher microvessel density in the FVPTCs group. A higher peripheral vessels distribution was observed only in malignant neoplasms. We observed overall Ras mutations in 2.4% of adenomas, in 41.5% of FVPTCs, and in 44.8% of FCs. It is outstanding that there is a marked difference in the Ras mutation distribution between the benign and malignant tumors in our series.
CONCLUSIONS: We found that genotyping of Ras gene family together with an accurate analysis of selected morphological features could help in the differential diagnosis of follicular-derived thyroid neoplasms.

Okamoto K, Kodama K, Takase K, et al.
Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models.
Cancer Lett. 2013; 340(1):97-103 [PubMed] Related Publications
RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.

Bansal M, Gandhi M, Ferris RL, et al.
Molecular and histopathologic characteristics of multifocal papillary thyroid carcinoma.
Am J Surg Pathol. 2013; 37(10):1586-91 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is frequently multifocal, which can represent either intraglandular spread from a single primary tumor or multiple synchronous primary tumors (MSPTs). To distinguish and characterize these entities, we investigated whether multifocal PTCs contain genetically similar or different mutations and have particular histopathologic characteristics. In 60 cases of PTC with 2 to 4 discrete tumor foci, each focus was tested for BRAF, NRAS, HRAS, and KRAS point mutations and RET/PTC1 and RET/PTC3 rearrangements and analyzed for various histopathologic features. Overall, BRAF mutations were found in 43% of tumors, RAS in 27%, and RET/PTC in 2%. Four different patterns of mutation occurrence were identified: (i) 2 foci containing different mutations (30%); (ii) 1 tumor containing a mutation and another carrying no mutations (32%); (iii) both/all tumors containing the same mutation (25%); (iv) all tumors having no mutations (13%). The 30% of cases with 2 different mutations represent a group of tumors that are unequivocally MSPT. These tumors more commonly occurred in different lobes, although they could be located as close as 0.6 cm from each other. Moreover, MSPTs typically demonstrated distinct histologic variants/microscopic features, were encapsulated or had a smooth border, and showed no microscopic peritumoral dissemination. In conclusion, we demonstrate that at least 30% of multifocal PTCs represent unequivocal MSPTs that develop through distinct molecular alterations and that as many as 60% of multifocal PTCs are likely MSPTs. Histopathologically, MSPTs are typically located in different lobes, have distinct growth patterns, and do not show microscopic peritumoral dissemination.

Wang R, Hu H, Pan Y, et al.
RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer.
J Clin Oncol. 2012; 30(35):4352-9 [PubMed] Related Publications
PURPOSE: The RET fusion gene has been recently described in a subset of non-small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene.
PATIENTS AND METHODS: We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected.
RESULTS: Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months.
CONCLUSION: RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.

Celestino R, Sigstad E, Løvf M, et al.
Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes.
Genes Chromosomes Cancer. 2012; 51(12):1154-64 [PubMed] Related Publications
Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8-PPARG fusion is present in the neoplastic lesions that have a follicular architecture-follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray-based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls-one thyroid cancer cell line (TPC-1) and two PTCs with known CCDC6-RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8-PPARG fusion genes in thyroid tumorigenesis.

Caria P, Dettori T, Frau DV, et al.
Simultaneous occurrence of PAX8-PPARg and RET-PTC3 rearrangements in a follicular variant of papillary thyroid carcinoma.
Am J Surg Pathol. 2012; 36(9):1415-20 [PubMed] Related Publications
Specific genotype-phenotype correlations have been identified in conventional-type papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). In contrast, the genetic alterations underlying the pathogenesis of the follicular variant of PTC (FV-PTC), which shares some clinicopathologic and molecular features with both PTC and FTC, remain to be clarified. This entity shows a PAX8-PPARg fusion gene (associated with FTC), more frequently than BRAF or RET-PTC alterations (associated with PTC). Herein, we report, for the first time, an FV-PTC with the simultaneous occurrence of both RET-PTC and PAX8-PPARg alterations. Neoplastic cells were of the wild type for BRAF and H,K,N-RAS, had an apparently normal karyotype by conventional cytogenetics, and had a balanced genome by array comparative genomic hybridization analysis. In fact, submicroscopic chromosome rearrangements producing RET-PTC3 and PAX8-PPARg chimeric genes were found by interphase fluorescence in situ hybridization. We demonstrated that these 2 genetic alterations coexisted in the same tumor and were confined to 2 different clones. Our findings indicate that molecular heterogeneity, although an uncommon phenomenon, may occur in thyroid carcinoma and demonstrate the coexistence in a case of FV-PTC not only of the histologic but also of the molecular features of both PTC (RET-PTC) and FTC (PAX8-PPARg).

FitzGerald LM, Zhang X, Kolb S, et al.
Investigation of the relationship between prostate cancer and MSMB and NCOA4 genetic variants and protein expression.
Hum Mutat. 2013; 34(1):149-56 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Two genome-wide association studies (GWAS) identified the β-microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow-up studies demonstrate that the variant allele directly affects expression of the MSMB-encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population-based study of 1,323 cases and 1,268 age-matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.

Gandhi M, Evdokimova V, Nikiforov YE
Frequency of close positioning of chromosomal loci detected by FRET correlates with their participation in carcinogenic rearrangements in human cells.
Genes Chromosomes Cancer. 2012; 51(11):1037-44 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
It has been well established that genes participating in oncogenic rearrangements are non-randomly positioned and frequently close to each other in human cell nuclei. However, the actual distance between these fusion partners has never been determined. The phenomenon of fluorescence resonance energy transfer (FRET) is observed when a donor fluorophore is close (<10 nm) to transfer some of it energy to an acceptor fluorophore. The aim of this study was to validate the use of FRET on directly labeled DNA molecules to assess the frequency of positioning at <10 nm distances between genes known to be involved in rearrangement and to correlate it with their probability to undergo rearrangement. In the validation experiments, the frequency of FRET-sensitized emission (SE) was found to be 93-96% between probes for the immediately adjacent chromosomal regions as compared to 0.1-0.2% between probes for the random loci located on large linear separation. Further, we found that the frequency of FRET-SE between four pairs of genes that form rearrangements in thyroid cancer was 5% for RET and CCDC6, 4% for RET and NCOA4, 2% for BRAF and AKAP9, and 2% for NTRK1 and TPR. Moreover, the frequency with which FRET was observed showed strong correlation (r = 0.9871) with the prevalence of respective rearrangements in thyroid cancer. Our findings demonstrate that FRET can be used as a technique to analyze proximity between specific DNA regions and that the frequency of gene positioning at distances allowing FRET correlates with their probability to undergo chromosomal rearrangements.

Grisanzio C, Werner L, Takeda D, et al.
Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis.
Proc Natl Acad Sci U S A. 2012; 109(28):11252-7 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.

Lou H, Li H, Yeager M, et al.
Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts.
Hum Genet. 2012; 131(9):1453-66 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.

Kwon EM, Holt SK, Fu R, et al.
Androgen metabolism and JAK/STAT pathway genes and prostate cancer risk.
Cancer Epidemiol. 2012; 36(4):347-53 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Prostate cancer (PC) is the most frequently diagnosed solid tumor in U.S. men. Genome-wide association studies (GWAS) have identified over 40 risk-associated single nucleotide polymorphisms (SNPs), including variants in androgen pathway genes (e.g., KLK3 and AR). Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC.
METHODS: In this hypothesis-testing study, we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor (AR). A total of 187 SNPs were genotyped in 1458 cases and 1351 age-matched controls from a population-based study. PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models.
RESULTS: Single SNP analyses showed evidence (p < 0.05) for associations with 14 SNPs in 9 genes: NKX3.1, HSD17B3, AKR1C3, SULT2A1, CYP17A1, KLK3, JAK2, NCOA4 and STAT3. The most significant result was observed for rs2253502 in HSD17B3 (odds ratio, OR = 0.57, 95% CI: 0.39-0.84). In addition, five SNPs in four genes (CYP17A1, HSD17B4, NCOA4, and SULT2A1) were associated with more aggressive disease (p < 0.01).
CONCLUSIONS: Our results replicate previously reported associations for SNPs in CYP17A1, HSD17B3, ARK1C3, NKX3.1, NCOA4 and KLK3. In addition, novel associations were observed for SNPs in JAK2, HSD17B4, and SULT2A1. These results will require replication in larger studies.

Dinets A, Hulchiy M, Sofiadis A, et al.
Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma.
Eur J Endocrinol. 2012; 166(6):1049-60 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Increased incidence of papillary thyroid carcinoma (PTC) is observed as a consequence of radiation exposure in connection to the Chornobyl nuclear plant accident in 1986. In this study, we report a cohort of adult Ukrainian patients diagnosed with PTC from 2004 to 2008 following exposure at the age of 18 years or younger.
METHODS: In total, 70 patients were identified and clinically characterized. The common BRAF 1799T>A mutation was assessed by pyrosequencing, the RET/PTC1 and RET/PTC3 (NCOA4) rearrangements by RT-PCR, and the expression of Ki-67 (MIB-1 index), BCL2, cyclin A, and cyclin D1 by immunohistochemistry.
RESULTS: In total, 46/70 (66%) cases carried a BRAF mutation and/or a RET/PTC rearrangement. A BRAF mutation was detected in 26 tumors, RET/PTC1 in 20 cases, and RET/PTC3 in four cases. In four of these cases, BRAF mutation and RET/PTC rearrangement were coexisting. The BRAF mutation was underrepresented among PTCs with accompanying chronic lymphocytic thyroiditis (CLT) compared with PTCs without this feature (12 vs 44%). MIB-1 proliferation index determined by double staining with leukocyte common antigen was low (mean 0.8%; range 0.05-4.5%). Moreover, increased expression of cyclin A was observed in PTCs with a tumor size >2 cm compared with PTCs ≤2 cm (1.2 vs 0.6%). BCL2 and cyclin D1 showed frequent expression but without associations to clinical characteristics or amplification of the CCND1 locus.
CONCLUSIONS: Our results suggest that this cohort has frequent BRAF mutation, RET/PTC1 rearrangement, and low proliferation index. Furthermore, BRAF 1799T>A was underrepresented in PTCs with CLT, and cyclin A expression was associated with increased PTC tumor size.

Gandhi M, Nikiforov YE
Suitability of animal models for studying radiation-induced thyroid cancer in humans: evidence from nuclear architecture.
Thyroid. 2011; 21(12):1331-7 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Rat and mouse have been widely used to estimate the radiation risk and tumorigenic effects of radiation with extrapolating the findings to humans. RET/PTC is a characteristic genetic alteration frequently found in radiation-induced thyroid cancer in human populations. Recently, nuclear architecture and spatial proximity between recombinogenic genes have been implicated as important factors in the generation of RET/PTC and other chromosomal rearrangements in human cells. However, it is unknown whether the nuclear architecture in rodent thyroid cells is similar to that of human thyroid cells. The aim of this study was to test whether the proximity effects that are observed between loci involved in RET/PTC rearrangements in humans are conserved across different species.
METHODS: Using 3D fixation, fluorescence in situ hybridization, and confocal microscopy, we compared the distance between genes involved in RET/PTC rearrangement in normal thyroid cells from humans, mice, and rats.
RESULTS: While in humans, RET, NCOA4, and H4 are all located on the same chromosome (10q), in rodents these genes are located on separate chromosomes. In mouse, RET is located on chromosome 6F1, NCOA4 on 14B, and H4 on 10B5.3. In rat, RET is on chromosome 4q42, NCOA4 on 16p16, and H4 (TST1) on 9q36. We further observed that in human thyroid cells, mean distance between genes involved in two most common types of RET/PTC, that is, RET and NCOA4 (partners of RET/PTC3) and RET and H4 (partners of RET/PTC1), was 1.08±0.04 and 1.24±0.05 μm, respectively. In mouse thyroid cells, these distances were 3.21±0.1 and 3.43±0.1 μm, and in rat cells the values were 3.37±0.1 and 3.87±0.1 μm (p<0.001). Moreover, we found that in contrast to human thyroid cells, in rodent cells these genes were randomly positioned with respect to each other.
CONCLUSIONS: The differences in nuclear architecture and spatial positioning of genes involved in RET/PTC rearrangements between human and rodent thyroid cells raise a concern about suitability of animal models for assessing RET/PTC-driven thyroid carcinogenesis in humans.

Abou-El-Ardat K, Monsieurs P, Anastasov N, et al.
Low dose irradiation of thyroid cells reveals a unique transcriptomic and epigenetic signature in RET/PTC-positive cells.
Mutat Res. 2012; 731(1-2):27-40 [PubMed] Related Publications
The high doses of radiation received in the wake of the Chernobyl incident and the atomic bombing of Hiroshima and Nagasaki have been linked to the increased appearance of thyroid cancer in the children living in the vicinity of the site. However, the data gathered on the effect of low doses of radiation on the thyroid remain limited. We have examined the genome wide transcriptional response of a culture of TPC-1 human cell line of papillary thyroid carcinoma origin with a RET/PTC1 translocation to various doses (0.0625, 0.5, and 4Gy) of X-rays and compared it to response of thyroids with a RET/PTC3 translocation and against wild-type mouse thyroids irradiated with the same doses using Affymetrix microarrays. We have found considerable overlap at a high dose of 4Gy in both RET/PTC-positive systems but no common genes at 62.5mGy. In addition, the response of RET/PTC-positive system at all doses was distinct from the response of wild-type thyroids with both systems signaling down different pathways. Analysis of the response of microRNAs in TPC-1 cells revealed a radiation-responsive signature of microRNAs in addition to dose-responsive microRNAs. Our results point to the fact that a low dose of X-rays seems to have a significant proliferative effect on normal thyroids. This observation should be studied further as opposed to its effect on RET/PTC-positive thyroids which was subtle, anti-proliferative and system-dependent.

Li X, Zhu C, Tu WH, et al.
ZMIZ1 preferably enhances the transcriptional activity of androgen receptor with short polyglutamine tract.
PLoS One. 2011; 6(9):e25040 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
The androgen receptor (AR) is a ligand-induced transcription factor and contains the polyglutamine (polyQ) tracts within its N-terminal transactivation domain. The length of polyQ tracts has been suggested to alter AR transcriptional activity in prostate cancer along with other endocrine and neurologic disorders. Here, we assessed the role of ZMIZ1, an AR co-activator, in regulating the activity of the AR with different lengths of polyQ tracts as ARQ9, ARQ24, and ARQ35 in prostate cancer cells. ZMIZ1, but not ZMIZ2 or ARA70, preferably augments ARQ9 induced androgen-dependent transcription on three different androgen-inducible promoter/reporter vectors. A strong protein-protein interaction between ZMIZ1 and ARQ9 proteins was shown by immunoprecipitation assays. In the presence of ZMIZ1, the N and C-terminal interaction of the ARQ9 was more pronounced than ARQ24 and ARQ35. Both Brg1 and BAF57, the components of SWI/SNF complexes, were shown to be involved in the enhancement of ZMIZ1 on AR activity. Using the chromatin immunoprecipitation assays (ChIP), we further demonstrated a strong recruitment of ZMIZ1 by ARQ9 on the promoter of the prostate specific antigen (PSA) gene. These results demonstrate a novel regulatory role of ZMIZ1 in modulating the polyQ tract length of AR in prostate cancer cells.

Geraldo MV, Yamashita AS, Kimura ET
MicroRNA miR-146b-5p regulates signal transduction of TGF-β by repressing SMAD4 in thyroid cancer.
Oncogene. 2012; 31(15):1910-22 [PubMed] Related Publications
MicroRNAs (miRNA) are small non-coding RNAs involved in post-transcriptional gene regulation that have crucial roles in several types of tumors, including papillary thyroid carcinoma (PTC). miR-146b-5p is overexpressed in PTCs and is regarded as a relevant diagnostic marker for this type of cancer. A computational search revealed that miR-146b-5p putatively binds to the 3' untranslated region (UTR) of SMAD4, an important member of the transforming growth factor β (TGF-β) signaling pathway. The TGF-β pathway is a negative regulator of thyroid follicular cell growth, and the mechanism by which thyroid cancer cells evade its inhibitory signal remains unclear. We questioned whether the modulation of the TGF-β pathway by miR-146b-5p can contribute to thyroid tumorigenesis. Luciferase reporter assay confirmed the direct binding of miR-146b-5p on the SMAD4 3'UTR. Specific inhibition of miR-146b-5p with a locked nucleic acid-modified anti-miR-146b oligonucleotide significantly increased SMAD4 levels in the human papillary carcinoma cell lines, TPC-1 and BCPAP. Moreover, suppression of miR-146b-5p increased the cellular response to the TGF-β anti-proliferative signal, significantly decreasing the proliferation rate. The overexpression of miR-146b-5p in normal rat follicular PCCL3 cells decreased SMAD4 levels and disrupted TGF-β signal transduction. MiR-146b-5p overexpression in PCCL3 cells also significantly increased cell proliferation in the absence of thyroid-stimulating hormone and conferred resistance to TGF-β-mediated cell-cycle arrest. Additionally, the activation of thyroid most common oncogenes RET/PTC3 and BRAF in PCCL3 cells upregulated miR-146b-5p expression. Our results confirm the oncogenic role of miR-146b-5p in thyroid follicular cells and contribute to knowledge regarding the modulation of TGF-β signal transduction by miRNAs in PTCs.

Wang Y, Li JQ, Shao C, et al.
Androgen receptor coregulators NOCR1, TIF2, and ARA70 may account for the hydroxyflutamide insensitivity of prostate cancer cells.
Ir J Med Sci. 2011; 180(4):865-72 [PubMed] Related Publications
INTRODUCTION: Prostate cancer cells can switch from an androgen-dependent state to an androgen-independent state after a continuous androgen ablation therapy. However, the molecular mechanisms underlying this switch are still unclear. Therefore, we explored the change in androgen receptor (AR)-related gene expression during this transition in a novel cell model.
MATERIAL AND METHODS: Prostate cancer cells were continuously treated with competitive androgen receptor inhibitor hydroxyflutamide for 1.5 years, which yielded an flutamide-insensitive LNCaP subline, LNCaP-flu, as confirmed by MTT assays, flow cytometry, and electron microscopy. We analyzed the differences in gene expression in LNCaP-flu cells and LNCaP cells using gene chips and follow-up RT-PCR.
RESULTS: Over 2,428 genes were differentially expressed between these cell lines: 1,194 were down-regulated and 1,234 were up-regulated. Three genes in particular were considered related to the androgen-dependent transition: NCOR1, TIF2 (NCOA2), and ARA70 (NCOA4). There were no apparent changes in expression of the androgen receptor or prostate-specific antigen.
CONCLUSION: ARs and associated coregulators play a central role in the flutamide-insensitive transition of prostate cancer cells. Although AR expression does not change during this transition, the change in AR coregulators may be a critical factor in the development of antiandrogen insensitivity.

Stanojevic B, Dzodic R, Saenko V, et al.
Mutational and clinico-pathological analysis of papillary thyroid carcinoma in Serbia.
Endocr J. 2011; 58(5):381-93 [PubMed] Related Publications
Molecular pathogenesis of papillary thyroid carcinoma (PTC) is largely associated with mutational changes in the BRAF, RAS family and RET genes. Our aim was to assess clinico-pathological and prognostic correlations of these PTC-specific gene alterations, with a particular emphasis on the BRAF mutation, in a group of 266 Serbian PTC patients, for the first time. The reference center-based retrospective cohort included 201 (75.6%) females and 65 (24.4%) males aged 48.0±16.1 years (8-83 years old, range) diagnosed and treated for PTC during 1993-2008. Follow-up period was 53.1±41.6 months (7-187 months, range). BRAF and RAS mutations were determined by direct sequencing of genomic DNA. RET/PTC rearrangements were analyzed by RT-PCR/Southern blotting. Genetic alterations were detected in 150/266 tumors (56.4%). One tumor displayed two genetic alterations. The BRAF(V600E) was found in 84/266 (31.6%) cases, RAS mutations in 11/266 (4.1%) and RET/PTC in 55/266 (20.7%; 42/266 (15.8%) RET/PTC1 and 13/266 (4.9%) RET/PTC3). On multivariate analysis BRAF(V600E) was associated with the classical papillary morphology (P = 0.05), the higher pT category (P = 0.05) and advanced clinical stage (P = 0.03). In a proportional hazard model, BRAF(V600E) did not appear to be an independent risk factor for the faster recurrence (P = 0.784). We conclude that under the extensive thyroid surgery and limited application of radioiodine ablation BRAF(V600E) may not be an indicator of poorer disease-free survival during the short to middle follow-up period. However, it has a potential to contribute to patients stratification into high- and low-risk groups.

Tronko M, Bogdanova T, Voskoboynyk L, et al.
Radiation induced thyroid cancer: fundamental and applied aspects.
Exp Oncol. 2010; 32(3):200-4 [PubMed] Related Publications
AIM: To describe the epidemiology and pathology of thyroid cancer in Ukraine, and to perform the molecular analysis of genetic alterations more frequently found to be associated to papillary carcinomas (PTC) in a selected group of PTC.
MATERIALS AND METHODS: Relationship between the thyroid cancer incidence and gender, age, and place of residence of subjects aged 0-18 years at the time of the Chernobyl accident (5427 subjects of thyroid cancer, among which 3996 (73.6%) were children aged 0 to 14 years at the time of the accident, and 1431 (26.3%) were adolescents aged 15 to 18 years was studied. Pathologically analyzed thyroid carcinomas were obtained from 640 patients (20-40 years old at the time of surgery and born before the Chernobyl accident), and from 90 patients (11-22 years old at the time of surgery and born after the accident). All patients were operated during 2006-2008. RET/PTC rearrangements and BRAF(V600E) mutation were analyzed in 35 cases of PTC.
RESULTS: A comparison between the thyroid cancer incidence rates in the 6 highest contaminated regions of Ukraine and in the other 21 regions shows the most significant difference between the rates for the last three years of follow-up, which confirms that a direct relationship is still present between the rise in thyroid cancer incidence and the post Chernobyl radiation exposure. Much lower incidence of thyroid cancer in subjects, who were born after the accident, additionally confirmed a direct relationship between the Chernobyl accident and thyroid cancer development at least in those who were aged up to 18 years at the time of the nuclear accident. Pathological results showed that with increasing latency the decrease has been noted in the percentage of PTC with solid structure, a decrease in invasive properties of tumors, as well as an increase in the percentage of PTC with papillary-follicular structure, encapsulated forms, and carcinomas measuring up to 1 cm. Molecular-biological studies of PTC revealed more common RET/PTC1 and RET/PTC3 rearrangements (34.3% of cases), than BRAFV600E mutation (24%cases).
CONCLUSION: After 22 years from the Chernobyl nuclear accident the number and incidence of thyroid cancer cases in Ukraine was steadily increased in the cohort of those who were children and adolescents at the time of the accident. Most common thyroid tumors (PTC) were characterized by significant changes in histological structure with increasing latency. PTC with any RET/PTC rearrangements had more aggressive behavior than BRAF(V600E)-positive tumors or PTC without gene alterations.

Wang XL, Kong F, Shen T, et al.
Sesquiterpenoids from myrrh inhibit androgen receptor expression and function in human prostate cancer cells.
Acta Pharmacol Sin. 2011; 32(3):338-44 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
AIM: To examine whether two naturally occurring sesquiterpenoids (ST1 and ST2) with anti-proliferative activity in prostate cancer cells inhibit androgen receptor (AR) signaling.
METHODS: Human prostate cancer cell lines LNCaP and PC3 were used. The expression of AR, AR translocation into the nucleus, and expression levels of AR coactivators ARA70 and steroid receptor coactivator-1 (SRC-1) in LNCaP cells were examined using real-time PCR and Western blot. Changes in prostate-specific antigen (PSA) protein levels, PSA promoter activity, and androgen response element (ARE)-mediated reporter gene activity were examined using enzyme-linked immunoabsorbent assay (ELISA) and transient transfection assays. Co-immunoprecipitation was performed to analyze the interaction between AR and the AR coactivators in ST1- and ST2-treated cells.
RESULTS: In LNCaP cells, ST1 and ST2 (40 μmol/L) led to a significant decrease in the expression of AR as well as a reduction of AR translocation into the nucleus, but had no effect on AR protein translation. ST1 and ST2 treatment also resulted in a significant decrease in the level of PSA protein secreted into the medium and was able to suppress PSA promoter-dependent and ARE-dependent luciferase activity. Furthermore, decreased expression of ARA70 and SRC-1 was observed when LNCaP cells were exposed to ST1 and ST2, which interfered with their ability to interact with AR.
CONCLUSION: The observations suggest that suppression of AR transactivation by ST1 and ST2 may be mediated, in part, by inhibiting AR nuclear translocation and/or interfering with the interaction between AR and its coactivators ARA70 and SRC-1. Therefore, sesquiterpenoids could be developed as novel therapeutic agents for treating prostate cancer.

Nacu S, Yuan W, Kan Z, et al.
Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples.
BMC Med Genomics. 2011; 4:11 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Readthrough fusions across adjacent genes in the genome, or transcription-induced chimeras (TICs), have been estimated using expressed sequence tag (EST) libraries to involve 4-6% of all genes. Deep transcriptional sequencing (RNA-Seq) now makes it possible to study the occurrence and expression levels of TICs in individual samples across the genome.
METHODS: We performed single-end RNA-Seq on three human prostate adenocarcinoma samples and their corresponding normal tissues, as well as brain and universal reference samples. We developed two bioinformatics methods to specifically identify TIC events: a targeted alignment method using artificial exon-exon junctions within 200,000 bp from adjacent genes, and genomic alignment allowing splicing within individual reads. We performed further experimental verification and characterization of selected TIC and fusion events using quantitative RT-PCR and comparative genomic hybridization microarrays.
RESULTS: Targeted alignment against artificial exon-exon junctions yielded 339 distinct TIC events, including 32 gene pairs with multiple isoforms. The false discovery rate was estimated to be 1.5%. Spliced alignment to the genome was less sensitive, finding only 18% of those found by targeted alignment in 33-nt reads and 59% of those in 50-nt reads. However, spliced alignment revealed 30 cases of TICs with intervening exons, in addition to distant inversions, scrambled genes, and translocations. Our findings increase the catalog of observed TIC gene pairs by 66%.We verified 6 of 6 predicted TICs in all prostate samples, and 2 of 5 predicted novel distant gene fusions, both private events among 54 prostate tumor samples tested. Expression of TICs correlates with that of the upstream gene, which can explain the prostate-specific pattern of some TIC events and the restriction of the SLC45A3-ELK4 e4-e2 TIC to ERG-negative prostate samples, as confirmed in 20 matched prostate tumor and normal samples and 9 lung cancer cell lines.
CONCLUSIONS: Deep transcriptional sequencing and analysis with targeted and spliced alignment methods can effectively identify TIC events across the genome in individual tissues. Prostate and reference samples exhibit a wide range of TIC events, involving more genes than estimated previously using ESTs. Tissue specificity of TIC events is correlated with expression patterns of the upstream gene. Some TIC events, such as MSMB-NCOA4, may play functional roles in cancer.

Mathur A, Weng J, Moses W, et al.
A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy.
Surgery. 2010; 148(6):1170-6; discussion 1176-7 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy.
METHODS: Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived.
RESULTS: By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups.
CONCLUSION: Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.

Pomerantz MM, Shrestha Y, Flavin RJ, et al.
Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.
PLoS Genet. 2010; 6(11):e1001204 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.

Zeindl-Eberhart E, Liebmann S, Jungblut PR, et al.
Influence of RET/PTC1 and RET/PTC3 oncoproteins in radiation-induced papillary thyroid carcinomas on amounts of cytoskeletal protein species.
Amino Acids. 2011; 41(2):415-25 [PubMed] Related Publications
Radiation-induced human papillary thyroid carcinomas (PTCs) show a high prevalence of fusions of the RET proto-oncogene to heterologous genes H4 (RET/PTC1) and ELE1 (RET/PTC3), respectively. In contrast to the normal membrane-bound RET protein, aberrant RET fusion proteins are constitutively active oncogenic cytosolic proteins that can lead to malignant transformation of thyroid epithelia. To detect specific tumor-associated protein changes that reflect the effect of RET/PTC fusion proteins, we analyzed normal thyroid tissues, thyroid tumors of the RET/PTC1 and RET/PTC3 type and their respective lymph node metastases by a combination of high-resolution two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-mass spectrometry. PTCs without RET rearrangements served as controls. Several cytoskeletal protein species showed quantitative changes in tumors and lymph node metastases harboring RET/PTC1 or RET/PTC3. We observed prominent C-terminal actin fragments assumedly generated by protease cleavages induced due to enhanced amounts of the active actin-binding protein cofilin-1. In addition, three truncated vimentin species, one of which was proven to be headless, were shown to be highly abundant in tumors and metastases of both RET/PTC types. The observed protein changes are closely connected with the constitutive activation of RET-rearranged oncoproteins and reflect the importance to elucidate disease-related typical signatures on the protein species level.

Neely RJ, Brose MS, Gray CM, et al.
The RET/PTC3 oncogene activates classical NF-κB by stabilizing NIK.
Oncogene. 2011; 30(1):87-96 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
The oncogenic fusion protein RET/PTC3 (RP3) that is expressed in papillary thyroid carcinoma (PTC) and thyroid epithelia in Hashimoto's thyroiditis activates nuclear factor-kappa B (NF-κB) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown. To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-κB signaling components. In wild-type MEFs, RP3 upregulated CCL2, CXCL1, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor expression and activated classical but not noncanonical NF-κB. RP3-activated NF-κB in IκB kinase (IKK)β(-/-) MEFs but not IKKα- or NF-κB essential modulator (NEMO)-deficient cells and activation was inhibited by a peptide that blocks NEMO binding to the IKKs. RP3 increased the levels of NF-κB-inducing kinase (NIK) and did not activate NF-κB in NIK-deficient MEFs. Notably, NIK stabilization was not accompanied by TRAF3 degradation demonstrating that RP3 disrupts normal basal NIK regulation. Dominant-negative NIK blocked RP3-induced NF-κB activation and an RP3 signaling mutant (RP3(Y588F)) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-κB via NIK, NEMO and IKKα. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-κB activation via stabilization of NIK.

Wu X, Chen F, Sahin A, et al.
Distinct function of androgen receptor coactivator ARA70α and ARA70β in mammary gland development, and in breast cancer.
Breast Cancer Res Treat. 2011; 128(2):391-400 [PubMed] Related Publications
Steroid receptor coactivators are important in regulating the function of the receptors in endocrine organ development and in cancers, including breast. Androgen receptor (AR) coactivator ARA70, was first identified as a gene fused to the ret oncogene and later characterized as an AR coactivator. We previously reported that the full length ARA70α functions as a tumor suppressor gene and that ARA70β functions as an oncogene in prostate cancer. Here we show that both ARA70α and ARA70β function as AR and estrogen receptor (ER) coactivators in breast cancer cells. However, ARA70α and ARA70β serve different functions in mammary gland development and breast cancer tumorigenesis. We observed hypoplastic development of mammary glands in MMTV driven ARA70α transgenic mice and overgrowth of mammary glands in ARA70β transgenic mice at virgin and pregnant stages. We determined that ARA70α inhibited cell proliferation, and that ARA70β promotes proliferation in MCF7 breast cancer cells. These effects were observed in hormone-free media, or in media with androgen or estrogen, though to varying degrees. Additionally, we observed that ARA70β strongly enhanced the invasive ability of MCF7 breast cancer cells in in vitro Matrigel assays. Significantly, decreased ARA70α expression is associated with increased tendency of breast cancer metastasis. In summary, ARA70α and ARA70β have distinct effects in mammary gland development and in the progression of breast cancer.

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