AREG

Gene Summary

Gene:AREG; amphiregulin
Aliases: AR, SDGF, AREGB, CRDGF
Location:4q13.3
Summary:The protein encoded by this gene is a member of the epidermal growth factor family. It is an autocrine growth factor as well as a mitogen for astrocytes, Schwann cells and fibroblasts. It is related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). The protein interacts with the EGF/TGF-alpha receptor to promote the growth of normal epithelial cells, and it inhibits the growth of certain aggressive carcinoma cell lines. It also functions in mammary gland, oocyte and bone tissue development. This gene is associated with a psoriasis-like skin phenotype, and is also associated with other pathological disorders, including various types of cancers and inflammatory conditions. [provided by RefSeq, Apr 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:amphiregulin
HPRD
Source:NCBIAccessed: 11 August, 2015

Ontology:

What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 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.

  • Amphiregulin
  • Tumor Markers
  • Proto-Oncogene Proteins
  • Transcriptional Activation
  • TGFA
  • Epiregulin
  • Estrogen Receptors
  • Colorectal Cancer
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Soft Tissue Cancers
  • Antineoplastic Agents
  • Up-Regulation
  • Epidermal Growth Factor Receptor
  • Oligonucleotide Array Sequence Analysis
  • Breast Cancer
  • Mutation
  • Gene Expression
  • EGF Family of Proteins
  • Cell Proliferation
  • Epidermal Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Gene Expression Profiling
  • Molecular Sequence Data
  • Receptor, erbB-2
  • Growth Substances
  • Androgen Receptors
  • Soft Tissue Sarcoma
  • Base Sequence
  • Antibodies, Monoclonal, Humanized
  • Monoclonal Antibodies
  • Glycoproteins
  • Survival Rate
  • Drug Resistance
  • FGFR1
  • Liver Cancer
  • Warts
  • Sequence Homology
  • Chromosome 4
  • Immunohistochemistry
  • Neoplasm Proteins
Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: AREG (cancer-related)

Tsvetkova A, Todorova A, Todorov T, et al.
Molecular and clinico-histological data in aggressive prostate cancer patients from Bulgaria.
J BUON. 2015 Mar-Apr; 20(2):498-504 [PubMed] Related Publications
PURPOSE: Metastatic prostate cancer (PCa) is one of the leading causes of death in men worldwide. We report Bulgarian patients with strongly aggressive, castration-resistant PCa.
METHODS: PCA3 overexpression, GSTP1 promoter hyper-methylation, TMPRSS2-ERG gene fusions, IVS1-27G>A in the KLF6 gene and mutations in androgen receptor (AR) gene, for diagnostic purposes were assessed. PCR, real-time PCR (RT-PCR), sequencing, and bisulfite conversion of DNA were applied. We correlated the molecular data to the histological and clinical findings.
RESULTS: The obtained molecular profile in 11 PCa Bulgarian patients coincided with the clinico-histological data of strongly aggressive PCa. Association was detected between the tumor stage (assessed by TNM as T3 and T4) and the detected molecular profile of aggressive cancer behavior with one exception, assessed as T2. None of our patients had positive family history of prostate cancer and no somatic mutations were detected in the AR gene. All patients showed normal genotype with respect to the KLF6 IVS1- 27G>A polymorphism. The rest of the markers were positive in fresh prostatic tissues and biopsies from all patients, whereas only one blood sample showed triple positive result.
CONCLUSIONS: The appearance of PCa-specific markers in blood was considered as a predictor for a PCa (micro) dissemination into the circulation. The GSTP1 promoter hypermethylation is the earliest epigenetic alteration, which indicates cancerous changes and the first and long-lasting marker that is detectable in blood circulation. The molecular profile needs to be strictly monitored during treatment, which is of great help in determining the patient's individual response to therapy.

Robinson D, Van Allen EM, Wu YM, et al.
Integrative clinical genomics of advanced prostate cancer.
Cell. 2015; 161(5):1215-28 [PubMed] Article available free on PMC after 21/05/2016 Related Publications
Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

Iobagiu C, Lambert C, Raica M, et al.
Loss of heterozygosity in tumor tissue in hormonal receptor genes is associated with poor prognostic criteria in breast cancer.
Cancer Genet. 2015; 208(4):135-42 [PubMed] Related Publications
The estrogen receptors (ESRα and β) and the androgen receptor (AR) mediate genomic and non-genomic effects on breast tumor growth and proliferation. We analyzed 101 breast cancer patients for allelic loss in microsatellites located in regulatory regions of the ESRs and AR genes in breast cancer tumors. The loss of heterozygosity (LOH) at these loci was found in 36.2% of tumor tissues (ductal carcinoma cases), for 19% of cases at the ESRα locus, for 16% at the ESRβ locus, and for 10% at the AR locus. The LOH in at least one of the two ESR loci was correlated to poor prognosis criteria: ESR-negative status (P = 0.007), PR-negative status (P = 0.003), high Scarff-Bloom-Richardson (SBR) grade (P = 0.0007), high MIB-1 proliferation index (P = 0.02), and diminished apoptosis potential (TP53-positive status, P = 0.018). When AR was also considered, the LOH in at least one of the three loci was associated with ESR-negative status (P = 0.036), PR-negative status (P = 0.027), high SBR grade (P = 0.005), high mitotic index (P = 0.0002), TP53-positive status (P = 0.029), and proliferating index (high MIB-1, P = 0.03). Allelic loss was observed in 26% of normal tissue adjacent to tumor with LOH at the ESRα locus and in 7.1% of tumors with LOH at the ESRβ locus. The LOH in tumor tissue in the regulatory regions of ESRα, ESRβ, and AR genes has potentially synergistic effects on tumor proliferation, histological aggressiveness, down-regulation of ESRα and progesterone receptor (PR) genes, and is an early genetic alteration in cancer that is possibly involved in passage to estrogen independence.

Moriarity BS, Otto GM, Rahrmann EP, et al.
A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.
Nat Genet. 2015; 47(6):615-24 [PubMed] Related Publications
Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.

Simper NB, Jones CL, MacLennan GT, et al.
Basal cell carcinoma of the prostate is an aggressive tumor with frequent loss of PTEN expression and overexpression of EGFR.
Hum Pathol. 2015; 46(6):805-12 [PubMed] Related Publications
Basal cell carcinoma (also referred to as adenoid cystic carcinoma) is a rare tumor of the prostate. Although largely characterized as indolent, poor outcomes have been reported in a considerable fraction of cases. As yet, optimum treatment strategies for this cancer have not been developed. This study investigates protein expression of common or potential molecular therapeutic targets and reports on the clinicopathological features of 9 new cases. We evaluated the expression of ERBB2, KIT, androgen receptor, PTEN, EGFR, ERG, and p53 via immunohistochemistry. We also examined EGFR amplification and TMPRSS2-ERG gene rearrangement by fluorescence in situ hybridization. The mean clinical follow-up was 44 months. We found that basal cell carcinoma behaved aggressively with almost one-half of the cases displaying high-risk pathologic features or local recurrence (44%). One patient died as a result of metastatic disease. The most consistent abnormalities included a loss of PTEN expression (56% of cases) and EGFR overexpression (67% of cases). EGFR overexpression occurred in the absence of gene amplification. The TMPRSS2-ERG rearrangement was not detected in any of the tumors studied, nor was ERG protein positivity identified by immunostaining. In addition, ERBB2, KIT, p53, and androgen receptor expressions were either absent or showed only weak, limited reactivity. Our results suggest that there is a high morbidity associated with this tumor, and more intense follow-up and additional treatment may be indicated. Furthermore, targeted therapies directed against the EGFR and PTEN proteins or their constitutive pathways may be promising for future clinical management.

Kouri FM, Hurley LA, Daniel WL, et al.
miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma.
Genes Dev. 2015; 29(7):732-45 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood-brain/blood-tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

Fernandez EV, Reece KM, Ley AM, et al.
Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells.
Mol Pharmacol. 2015; 87(6):1006-12 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 α (HIF-1α) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1α target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1α inhibition attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth.

Wang F, Pan J, Liu Y, et al.
Alternative splicing of the androgen receptor in polycystic ovary syndrome.
Proc Natl Acad Sci U S A. 2015; 112(15):4743-8 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen-induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.

Guo W, Keener AL, Jing Y, et al.
FOXA1 modulates EAF2 regulation of AR transcriptional activity, cell proliferation, and migration in prostate cancer cells.
Prostate. 2015; 75(9):976-87 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
BACKGROUND: ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor in the prostate. However, the mechanisms underlying tumor suppressive function of EAF2 are still largely unknown. Identification of factors capable of modulating EAF2 function will help elucidate the mechanisms underlying EAF2 tumor suppressive function.
METHODS: Using eaf-1(the ortholog of EAF2) mutant C. elegans model, RNAi screen was used to identify factors on the basis of their knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans. In human cells, the interaction of EAF2 with FOXA1 and the effect of EAF2 on the FOXA1 protein levels were determined by co-immunoprecipitation and protein stability assay. The effect of EAF2 and/or FOXA1 knockdown on the expression of AR-target genes was determined by real-time RT-PCR and luciferase reporter assays. The effect of EAF2 and/or FOXA1 knockdown on LNCaP human prostate cancer cell proliferation and migration was tested using BrdU assay and transwell migration assay.
RESULTS: RNAi screen identified pha-4, the C. elegans ortholog of mammalian FOXA1, on the basis of its knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans causing sterility. EAF2 co-immunoprecipitated with FOXA1. EAF2 knockdown enhanced endogenous FOXA1 protein level, whereas transfected GFP-EAF2 down-regulated the FOXA1 protein. Also, EAF2 knockdown enhanced the expression of AR-target genes, cell proliferation, and migration in LNCaP cells. However, FOXA1 knockdown inhibited the effect of EAF2 knockdown on AR-target gene expression, cell proliferation, and migration in LNCaP cells, suggesting that FOXA1 can modulate EAF2 regulation of AR transcriptional activation, cell proliferation, and migration.
CONCLUSIONS: These findings suggest that regulation of the AR signaling pathway, cell proliferation, and migration through FOXA1 represents an important mechanism of EAF2 suppression of prostate carcinogenesis.

Liu YN, Yin J, Barrett B, et al.
Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis.
Mol Cell Biol. 2015; 35(11):1940-51 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.

Xiang Z, Abdallah AO, Govindarajan R, et al.
MYC amplification in multiple marker chromosomes and EZH2 microdeletion in a man with acute myeloid leukemia.
Cancer Genet. 2015; 208(3):96-100 [PubMed] Related Publications
The role of MYC and EZH2 in acute myeloid leukemia (AML) pathogenesis is poorly understood. Herein we present a case of AML with MYC amplification in marker chromosomes and a microdeletion of chromosome 7 below cytogenetic resolution. The karyotype of the patient's bone marrow aspirate showed three to five marker chromosomes in all dividing cells without other structural or numerical chromosomal abnormalities. Analysis by fluorescence in situ hybridization (FISH) with a probe specific for the human MYC gene revealed amplification of the oncogene localized to the marker chromosomes. Using whole genome single nucleotide polymorphism (SNP) microarray analysis, an approximately 4.4 Mb amplicon containing the MYC gene was identified with an estimated amplification of about 30 copies per leukemic cell and, thus, an average of about 8 copies per marker chromosome. A 6.4 Mb hemizygous microdeletion of chromosome 7 within band q36.1 was also found by SNP microarray analysis in a cellular-equivalent dosage of 50%. The microdeletion spans multiple genes, including EZH2, a gene with well-known cancer association. No mutation was found in the remaining EZH2 allele by next generation gene sequencing. The combination of MYC amplification and EZH2 deletion, which has not been described previously in AML, may suggest a synergistic role of the two oncogenes in the pathogenesis of the patient's acute leukemia.

Wang Y, Wu X, Ou L, et al.
PLCε knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor.
Cancer Lett. 2015; 362(1):61-9 [PubMed] Related Publications
Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.

Graham MK, Brown TR, Miller PS
Targeting the human androgen receptor gene with platinated triplex-forming oligonucleotides.
Biochemistry. 2015; 54(13):2270-82 [PubMed] Related Publications
Platinum-derivatized homopyrimidine triplex-forming oligonucleotides (Pt-TFOs) consisting of 2'-O-methyl-5-methyluridine, 2'-O-methyl-5-methylcytidine, and a single 3'-N7-trans-chlorodiammine platinum(II)-2'-deoxyguanosine were designed to cross-link to the transcribed strand at four different sequences in the human androgen receptor (AR) gene. Fluorescence microscopy showed that a fluorescein-tagged Pt-TFO localizes in both the cytoplasm and nucleus when it is transfected into LAPC-4 cells, a human prostate cancer cell line, using Lipofectamine 2000. A capture assay employing streptavidin-coated magnetic beads followed by polymerase chain reaction (PCR) amplification was used to demonstrate that 5'-biotin-conjugated Pt-TFOs cross-link in vitro to their four designated AR gene targets in genomic DNA extracted from LAPC-4 cells. Similarly, the capture assay was used to examine cross-linking between the 5'-biotin-conjugated Pt-TFOs and the AR gene in LAPC-4 cells in culture. Three of the four Pt-TFOs cross-linked to their designated target, suggesting that different regions of the AR gene are not uniformly accessible to Pt-TFO cross-linking. LAPC-4 cells were transfected with fluorescein-tagged Pt-TFO or a control oligonucleotide that does not bind or cross-link to AR DNA. The levels of AR mRNA in highly fluorescent cells isolated by fluorescence-activated cell sorting were determined by RT-qPCR, and the levels of AR protein were monitored by immunofluorescence microscopy. Decreases in mRNA and protein levels of 40 and 30%, respectively, were observed for fluorescein-tagged Pt-TFO versus control treated cells. Although the levels of knockdown of AR mRNA and protein were modest, the results suggest that Pt-TFOs hold potential as agents for controlling gene expression by cross-linking to DNA and disrupting transcription.

Yang S, Zhang J, Zhang Y, et al.
KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation.
Prostate. 2015; 75(9):936-46 [PubMed] Related Publications
BACKGROUND: Androgen receptor (AR) is a ligand dependent transcription factor that regulates the transcription of target genes. AR activity is closely involved in the maintenance and progression of prostate cancer. After the binding with androgen, AR moves into nucleus and binds to DNA sequence containing androgen response elements (ARE). Flavin-dependent monoamine oxidase KDM1A is necessary for AR driven transcription while the mechanism remains unclear.
METHODS: The association between androgen-dependent transcription and oxidation was tested through pharmaceutical inhibitions and siRNA knockdown of DNA oxidation repair components in prostate cancer cells. The recruitment of involved proteins and the histone methylation dynamics on ARE region was explored by chromatin immunoprecipitation (ChIP).
RESULTS: Oxidation inhibition reduced AR dependent expression of KLK3, TMPRSS2, hsa-miR-125b2, and hsa-miR-133b. And such reduction could be restored by H2 O2 treatment. KDM1A recruitment and H3K4me2 demethylation on ARE regions, which produce H2 O2 , are associated with AR targets transcription. AR targets transcription and coupled oxidation recruit 8-oxoguanine-DNA glycosylase (OGG1) and the nuclease APEX1 to ARE regions. Such recruitment depends on KDM1A, and is necessary for AR targets transcription.
CONCLUSION: Our work underlined the importance of histone demethylation and DNA oxidation/repairing machinery in androgen-dependent transcription. The present finds have implications for research into new druggable targets for prostate cancer relying on the cascade of AR activity regulation.

Couto JA, Vivero MP, Kozakewich HP, et al.
A somatic MAP3K3 mutation is associated with verrucous venous malformation.
Am J Hum Genet. 2015; 96(3):480-6 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non-hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM_002401.3, c.1323C>G; NP_002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans.

Oshimori N, Oristian D, Fuchs E
TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma.
Cell. 2015; 160(5):963-76 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Subsets of long-lived, tumor-initiating stem cells often escape cancer therapies. However, sources and mechanisms that generate tumor heterogeneity and drug-resistant cell population are still unfolding. Here, we devise a functional reporter system to lineage trace and/or genetic ablate signaling in TGF-β-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-β's impact on malignant progression, we demonstrate that TGF-β concentrating near tumor-vasculature generates heterogeneity in TGF-β signaling at tumor-stroma interface and bestows slower-cycling properties to neighboring SCC-SCs. While non-responding progenies proliferate faster and accelerate tumor growth, TGF-β-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-β-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-β transcriptionally activates p21, which stabilizes NRF2, thereby markedly enhancing glutathione metabolism and diminishing effectiveness of anti-cancer therapeutics. Together, these findings establish a surprising non-genetic paradigm for TGF-β signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance.

Chung BM, Arutyunov A, Ilagan E, et al.
Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes.
J Cell Biol. 2015; 208(5):613-27 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
High levels of the intermediate filament keratin 17 (K17) correlate with a poor prognosis for several types of epithelial tumors. However, the causal relationship and underlying mechanisms remain undefined. A recent study suggested that K17 promotes skin tumorigenesis by fostering a specific type of inflammation. We report here that K17 interacts with the RNA-binding protein hnRNP K, which has also been implicated in cancer. K17 is required for the cytoplasmic localization of hnRNP K and for its role in regulating the expression of multiple pro-inflammatory mRNAs. Among these are the CXCR3 ligands CXCL9, CXCL10, and CXCL11, which together form a signaling axis with an established role in tumorigenesis. The K17-hnRNP K partnership is regulated by the ser/thr kinase RSK and required for CXCR3-dependent tumor cell growth and invasion. These findings functionally integrate K17, hnRNP K, and gene expression along with RSK and CXCR3 signaling in a keratinocyte-autonomous axis and provide a potential basis for their implication in tumorigenesis.

Mousavi S, Panjehpour M, Izadpanahi MH, Aghaei M
Expression of adenosine receptor subclasses in malignant and adjacent normal human prostate tissues.
Prostate. 2015; 75(7):735-47 [PubMed] Related Publications
BACKGROUND: Adenosine, a purine nucleoside plays important roles in the pathogenesis of cancer initiation and promotion via interaction with four adenosine receptors. In the present study we examined the differential expression pattern of adenosine receptors in the malignant and adjacent normal human prostate tissues.
METHODS: Prostate cancer tissue samples and adjacent normal tissues were obtained from 20 patients undergoing radical prostatectomy and histopathological diagnosis was confirmed for each sample. Total RNA was extracted and reverse transcribed into cDNA and the mRNA expression levels of adenosine receptors were investigated by Taq-man real-time RT-PCR experiment. Quantitative protein analysis was done by Western blotting experiment. Moreover, the mRNA and protein expression levels of adenosine receptors were measured after androgen treatment.
RESULT: Taq-man real-time RT-PCR measurements show different expression levels of adenosine receptor transcripts. A2B adenosine receptor was predominantly expressed in tumor tissues (2.4-fold) followed by significantly expression of A3 (1.6-fold) and A2A adenosine receptors (1.5-fold) compared to adjacent normal tissues. The presence of adenosine receptors at protein levels in prostate cancer tissues compared with normal tissues was shown the following rank order: A2B  > A3  > A2A  > A1 . Androgen receptor regulates adenosine receptors mRNA and protein expression in AR-positive LNCaP cells, which was not seen in AR-negative PC-3 cells.
CONCLUSION: These results indicated for the first time, the differential mRNA expression profile and protein levels of adenosine receptors in the human prostate cancer. Interestingly, the A2B adenosine receptor followed by A3 is highly expressed in prostate tumor samples in comparison with the adjacent normal tissues. The findings support the possible key role of A2B adenosine receptor in promoting cancer cell growth and suggest that A2B may be a novel target for prostate cancer treatment.

Nasti TH, Rudemiller KJ, Cochran JB, et al.
Immunoprevention of chemical carcinogenesis through early recognition of oncogene mutations.
J Immunol. 2015; 194(6):2683-95 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), often harbor an H-ras point mutation, suggesting that it is a poor target for early immunosurveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as 1 d after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope-specific CTLs capable of eliminating Mut H-ras(+) preneoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective owing to insufficient effector pool size and/or immunosuppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I epitope-focused lentivector-infected dendritic cell- and DNA-based vaccines were designed to bias toward CTL rather than regulatory T cell induction. Mut H-ras, but not wild-type H-ras, epitope-focused vaccination generated specific CTLs and inhibited DMBA-induced tumor initiation, growth, and progression in preventative and therapeutic settings. Transferred Mut H-ras-specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor-bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes in expanding relevant immunosurveillance effectors to block tumor formation, rather than treating established tumors.

Wong LI, Labrecque MP, Ibuki N, et al.
p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) repress prostate specific antigen levels in human prostate cancer cell lines.
Chem Biol Interact. 2015; 230:40-9 [PubMed] Related Publications
Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disrupting chemicals, DDT and DDE are still ubiquitous in the environment. However, little attention has been directed to p,p'-DDT and the anti-androgen, p,p'-DDE on androgen receptor (AR) target gene transcription in human cells. Inhibitors of androgenic activity may have a deleterious clinical outcome in prostate cancer screens and progression, therefore we determined whether environmentally relevant concentrations of p,p'-DDT and p,p'-DDE negatively impact AR-regulated expression of prostate-specific antigen (PSA), and other AR target genes in human LNCaP and VCaP prostate cancer cells. Quantitative real-time PCR and immuno-blotting techniques were used to measure intracellular PSA, PSMA and AR mRNA and protein levels. We have shown for the first time that p,p'-DDT and p,p'-DDE repressed R1881-inducible PSA mRNA and protein levels in a dose-dependent manner. Additionally, we used the fully automated COBAS PSA detection system to determine that extracellular PSA levels were also significantly repressed. These chemicals achieve this by blocking the recruitment of AR to the PSA promoter region at 10 μM, as demonstrated by the chromatin immunoprecipitation (ChIP) in LNCaP cells. Both p,p'-DDT and p,p'-DDE repressed R1881-inducible AR protein accumulation at 10 μM. Thus, we conclude that men who have been exposed to either DDT or DDE may produce a false-negative PSA test when screening for prostate cancer, resulting in an inaccurate clinical diagnosis. More importantly, prolonged exposure to these anti-androgens may mimic androgen ablation therapy in individuals with prostate cancer, thus exacerbating the condition by inadvertently forcing adaptation to this stress early in the disease.

Lu J, Van der Steen T, Tindall DJ
Are androgen receptor variants a substitute for the full-length receptor?
Nat Rev Urol. 2015; 12(3):137-44 [PubMed] Related Publications
Androgen receptor splice variants (AR-Vs)--which are expressed in castration-resistant prostate cancer (CRPC) cell lines and clinical samples--lack the C-terminal ligand-binding domain and are constitutively active. AR-Vs are, therefore, resistant to traditional androgen deprivation therapy (ADT). AR-Vs are induced by several mechanisms, including ADT, and might contribute to the progression of CRPC and resistance to ADT. AR-Vs could represent a novel therapeutic target for prostate cancer, especially in CRPC.

Chen Y, Terajima M, Yang Y, et al.
Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.
J Clin Invest. 2015; 125(3):1147-62 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.

Khan R, Apewokin S, Grazziutti M, et al.
Renal insufficiency retains adverse prognostic implications despite renal function improvement following Total Therapy for newly diagnosed multiple myeloma.
Leukemia. 2015; 29(5):1195-201 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
Renal insufficiency (RI) is a frequent complication of multiple myeloma (MM) with negative consequences for patient survival. The improved clinical outcome with successive Total Therapy (TT) protocols was limited to patients without RI. We therefore performed a retrospective analysis of overall survival, progression-free survival and time to progression (TTP) of patients enrolled in TT2 and TT3 in relationship to RI present at baseline and pre-transplant. Glomerular filtration rate was graded in four renal classes (RCs), RC1-RC4 (RC1 ⩾90 ml/min/1.73 m(2), RC2 60-89 ml/min/1.73 m(2), RC3 30-59 ml/min/1.73 m(2) and RC4 <30 ml/min/1.73 m(2)). RC1-3 had comparable clinical outcomes while RC4 was deleterious, even after improvement to better RC after transplant. Among the 85% of patients with gene expression profiling defined low-risk MM, Cox regression modeling of baseline and pre-transplant features, which also took into consideration RC improvement and MM complete response (CR), identified the presence of metaphase cytogenetic abnormalities and baseline RC4 as independent variables linked to inferior TTP post-transplant, while MM CR reduced the risk of progression and TTP by more than 60%. Failure to improve clinical outcomes despite RI improvement suggested MM-related causes. Although distinguishing RC4 from RC<4, 46 gene probes bore no apparent relationship to MM biology or survival.

Gang X, Wang G, Huang H
Androgens regulate SMAD ubiquitination regulatory factor-1 expression and prostate cancer cell invasion.
Prostate. 2015; 75(6):561-72 [PubMed] Related Publications
BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed male cancer in the United States and is a hormone-driven disease. Androgens have been recognized as a major promoter of PCa development and progression. However, the mechanism of androgen action in PCa, especially in PCa cell invasion and metastasis remains largely unclear. SMAD ubiquitination regulatory factor-1 (SMURF1) is a C2-WW-HECT-domain E3 ubiquitin ligase that plays important roles in cancer cell metastasis. Whether there is a relationship between androgens and SMURF1 expression is not known.
METHODS: The effect of androgens on the expression of SMURF1 in PCa cell lines was examined by Western blot analyses and reverse transcription-polymerase chain reaction (RT-PCR). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied. The binding of AR to the SMURF1 gene enhancer was determined by chromatin immunoprecipitation (ChIP) assay. Cell migration and invasion was measured by wound healing and Matrigel invasion assays, respectively.
RESULTS: We found that expression of SMURF1 is upregulated by androgens in PCa cell lines and that this effect of androgens is mediated through the androgen receptor (AR). We further showed that androgens regulate SMURF1 expression at transcriptional level and provided evidence that AR transcriptionally activates SMURF1 by binding to its enhancer that contains a canonical half androgen responsive element (ARE). Finally, we demonstrated that SMURF1 is important for androgen-induced invasion of PCa cells.
CONCLUSIONS: We demonstrate for the first time that SMURF1 is a bona fide target gene of the AR. Our findings also suggest a potential role of SMURF1 in PCa metastasis.

Hallberg AR, Vorrink SU, Hudachek DR, et al.
Aberrant CpG methylation of the TFAP2A gene constitutes a mechanism for loss of TFAP2A expression in human metastatic melanoma.
Epigenetics. 2014; 9(12):1641-7 [PubMed] Related Publications
Metastatic melanoma is a deadly treatment-resistant form of skin cancer whose global incidence is on the rise. During melanocyte transformation and melanoma progression the expression profile of many genes changes. Among these, a gene implicated in several steps of melanocyte development, TFAP2A, is frequently silenced; however, the molecular mechanism of TFAP2A silencing in human melanoma remains unknown. In this study, we measured TFAP2A mRNA expression in primary human melanocytes compared to 11 human melanoma samples by quantitative real-time RT-PCR. In addition, we assessed CpG DNA methylation of the TFAP2A promoter in these samples using bisulfite sequencing. Compared to primary melanocytes, which showed high TFAP2A mRNA expression and no promoter methylation, human melanoma samples showed decreased TFAP2A mRNA expression and increased promoter methylation. We further show that increased CpG methylation correlates with decreased TFAP2A mRNA expression. Using The Cancer Genome Atlas, we further identified TFAP2A as a gene displaying among the most decreased expression in stage 4 melanomas vs. non-stage 4 melanomas, and whose CpG methylation was frequently associated with lack of mRNA expression. Based on our data, we conclude that TFAP2A expression in human melanomas can be silenced by aberrant CpG methylation of the TFAP2A promoter. We have identified aberrant CpG DNA methylation as an epigenetic mark associated with TFAP2A silencing in human melanoma that could have significant implications for the therapy of human melanoma using epigenetic modifying drugs.

Lee JH, Isayeva T, Larson MR, et al.
Endostatin: A novel inhibitor of androgen receptor function in prostate cancer.
Proc Natl Acad Sci U S A. 2015; 112(5):1392-7 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
Acquired resistance to androgen receptor (AR)-targeted therapies compels the development of novel treatment strategies for castration-resistant prostate cancer (CRPC). Here, we report a profound effect of endostatin on prostate cancer cells by efficient intracellular trafficking, direct interaction with AR, reduction of nuclear AR level, and down-regulation of AR-target gene transcription. Structural modeling followed by functional analyses further revealed that phenylalanine-rich α1-helix in endostatin-which shares structural similarity with noncanonical nuclear receptor box in AR-antagonizes AR transcriptional activity by occupying the activation function (AF)-2 binding interface for coactivators and N-terminal AR AF-1. Together, our data suggest that endostatin can be recognized as an endogenous AR inhibitor that impairs receptor function through protein-protein interaction. These findings provide new insights into endostatin whose antitumor effect is not limited to inhibiting angiogenesis, but can be translated to suppressing AR-mediated disease progression in CRPC.

Tsui KH, Chung LC, Feng TH, et al.
Divergent effect of liver X receptor agonists on prostate-specific antigen expression is dependent on androgen receptor in prostate carcinoma cells.
Prostate. 2015; 75(6):603-15 [PubMed] Related Publications
BACKGROUND: Liver X receptor (LXR) isoforms, LXRα and LXRβ, have similar protein structures and ligands, but diverse tissue distribution. We used two synthetic, non-steroidal LXR agonists, T0901317 and GW3965, to investigate the effects of LXR agonist modulation on prostate specific antigen (PSA) via the expressions of androgen receptors (AR), LXRα, or LXRβ, in prostate carcinoma cells.
METHODS: LXRα- or LXRβ-knockdown cells were transduced with specific shRNA lentiviral particles. LXRα and LXRβ expressions were assessed by immunoblotting and RT-qPCR assays. Cell proliferation was determined by (3) H-thymidine incorporation assays. The effects of LXR agonists and epigallocatechin gallate (EGCG) on PSA expression were determined by ELISA, immunoblotting, or transient gene expression assays.
RESULTS: Treatment with either T0901317 or GW3965 significantly attenuated cell proliferation of LNCaP cells. T0901317 treatment suppressed PSA expression while GW3965 treatment enhanced PSA expression. The increase of PSA promoter activity by GW3965 was dependent on the expression of AR. Either LXRα- or LXRβ-knockdown did not affect the activation of androgen on PSA gene expression. However, as compared with mock knockdown-LNCaP cells, the LXRα-knockdown but not the LXRβ-knockdown attenuated the effects of T0901317 and GW3965 on PSA expressions. The effect of GW3965 on PSA expression was blocked by the addition of EGCG.
CONCLUSIONS: Our results indicate that T0901317 and GW3965 have divergent effects on PSA expressions. The effects of LXR agonists on PSA expression are LXRα-dependent and AR-dependent. EGCG blocks the inducing effect of GW3965 on PSA expression.

Toropainen S, Malinen M, Kaikkonen S, et al.
SUMO ligase PIAS1 functions as a target gene selective androgen receptor coregulator on prostate cancer cell chromatin.
Nucleic Acids Res. 2015; 43(2):848-61 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
Androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in the development and growth of prostate carcinoma. PIAS1 is an AR- and SUMO-interacting protein and a putative transcriptional coregulator overexpressed in prostate cancer. To study the importance of PIAS1 for the androgen-regulated transcriptome of VCaP prostate cancer cells, we silenced its expression by RNAi. Transcriptome analyses revealed that a subset of the AR-regulated genes is significantly influenced, either activated or repressed, by PIAS1 depletion. Interestingly, PIAS1 depletion also exposed a new set of genes to androgen regulation, suggesting that PIAS1 can mask distinct genomic loci from AR access. In keeping with gene expression data, silencing of PIAS1 attenuated VCaP cell proliferation. ChIP-seq analyses showed that PIAS1 interacts with AR at chromatin sites harboring also SUMO2/3 and surrounded by H3K4me2; androgen exposure increased the number of PIAS1-occupying sites, resulting in nearly complete overlap with AR chromatin binding events. PIAS1 interacted also with the pioneer factor FOXA1. Of note, PIAS1 depletion affected AR chromatin occupancy at binding sites enriched for HOXD13 and GATA motifs. Taken together, PIAS1 is a genuine chromatin-bound AR coregulator that functions in a target gene selective fashion to regulate prostate cancer cell growth.

Booth L, Roberts JL, Cash DR, et al.
GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.
J Cell Physiol. 2015; 230(7):1661-76 [PubMed] Article available free on PMC after 02/09/2015 Related Publications
The chaperone GRP78/Dna K is conserved throughout evolution down to prokaryotes. The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes. Similar data with the drug combination were obtained for: HSP70, HSP90, GRP94, GRP58, HSP27, HSP40 and HSP60. OSU-03012/sildenafil treatment killed brain cancer stem cells and decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola/Marburg/Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Chikungunya, Mumps, Measles, Rubella, RSV, CMV, and Influenza viruses. OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression. The PDE5 inhibitors sildenafil or tadalafil enhanced OSU-03012 killing in N. gonorrhoeae and MRSE and low marginally toxic doses of OSU-03012 could restore bacterial sensitivity in N. gonorrhoeae to multiple antibiotics. Thus, Dna K and bacterial phosphodiesterases are novel antibiotic targets, and inhibition of GRP78 is of therapeutic utility for cancer and also for bacterial and viral infections.

Kizilay F, Kalemci MS, Şimşir A, et al.
The place of androgen receptor gene mutation analysis in the molecular diagnosis of prostate cancer and genotype-phenotype relationship.
Turk J Med Sci. 2014; 44(2):261-6 [PubMed] Related Publications
AIM: To determine the relationship between androgen receptor (AR) gene polymorphism and prostate cancer in our society.
MATERIALS AND METHODS: Thirty-nine patients diagnosed with prostate cancer and 34 benign prostatic hyperplasia (BPH) patients who were diagnosed in 2010 met the study criteria. The inclusion criteria included patients whose diagnosis was confirmed with a biopsy, with the presence of adequate pathologic material for review, between the ages of 40 and 80, and who were healthy men without a family history of prostate cancer. The exclusion criteria excluded men diagnosed with another cancer and those who had kin with a history of prostate cancer. A direct DNA sequencing method was utilized for detection of polymorphisms.
RESULTS: CAG repeat length varied from 13 to 28 (mean: 21.67) for the BPH group and 12 to 28 (mean: 21.74) for the prostate cancer group. Prostate-specific antigen (PSA) density and the androgen receptor (AR) CAG repeat had a statistically significant negative correlation in the BPH group. A statistically significant difference was associated between AR CAG repeat and PSA density.
CONCLUSION: Randomized prospective studies should be planned with larger patient and control groups and with more variables, which may open new horizons in prostate cancer screening and early detection.

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