ERBB4; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 (2q33.3-q34)

Gene Summary

Gene:ERBB4; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4
Aliases: HER4, ALS19, p180erbB4
Summary:This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:receptor tyrosine-protein kinase erbB-4
Updated:14 December, 2014


What does this gene/protein do?
Show (61)


What pathways are this gene/protein implicaed in?
- g-Secretase mediated ErbB4 Signaling Pathway BIOCARTA
- Role of ERBB2 in Signal Transduction and Oncology BIOCARTA
- Calcium signaling pathway KEGG
- Dorso-ventral axis formation KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 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.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (5)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerERBB4 and Breast Cancer View Publications40
Lung CancerERBB4 and Lung Cancer View Publications12
MelanomaERBB4 and Melanoma View Publications11
Prostate CancerERBB4 and Prostate Cancer View Publications10
Brain, MedulloblastomaERBB4 and Medulloblastoma View Publications3

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

Related Links

Latest Publications: ERBB4 (cancer-related)

Peters S, Zimmermann S, Adjei AA
Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions.
Cancer Treat Rev. 2014; 40(8):917-26 [PubMed] Related Publications
The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.

Related: Non-Small Cell Lung Cancer Lung Cancer EGFR

Kai Y, Peng W, Ling W, et al.
Reciprocal effects between microRNA-140-5p and ADAM10 suppress migration and invasion of human tongue cancer cells.
Biochem Biophys Res Commun. 2014; 448(3):308-14 [PubMed] Related Publications
ADAM10, overexpressed in tongue squamous cell carcinoma (TSCC), has been well documented for its role in tumor progression and metastasis. In the present study, we evaluated the inhibition effect of microRNAs (miRNAs) on the TSCC and identified that miR-140-5p could directly targets ADAM10 and inhibits the invasion and migration of TSCC cells. LAMC1, HDAC7 and PAX6, clustered into migration-related genes, were validated to be direct targets of miR-140-5p, while IGF1R and PSEN1 were not responsible to the regulation. Most intriguingly, ERBB4 was upregulated by miR-140-5p even though the interaction between ERBB4 3'UTR and miR-140-5p existed simultaneously. Meanwhile, ADAM10 is involved in the "positive" regulation of ERBB4 and negative regulation of PAX6 by miR-140-5p. Taken together, our results suggest that miR-140-5p play a role in TSCC cell migration and invasion, and two brand new relationships between miRNA and its targets emerged: (1) ADAM10 is not just a direct target of miR-140-5p, the repressed ADAM10 also helps to enhance the effect of miR-140-5p to other target genes: ERBB4 and PAX6; (2) ERBB4 is "positively" regulated by miR-140-5p.

Gasparini P, Fassan M, Cascione L, et al.
Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options.
PLoS One. 2014; 9(2):e88525 [PubMed] Free Access to Full Article Related Publications
Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival) and pathological (basal, non-basal subtype, stage, grade) features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases), especially in African American women (16.7% vs 25.5% of cancers of white women). No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01) and associated with better overall patient survival (p = 0.032) in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6) showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01). These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.

Related: AR: androgen receptor

Mirkina I, Hadzijusufovic E, Krepler C, et al.
Phenotyping of human melanoma cells reveals a unique composition of receptor targets and a subpopulation co-expressing ErbB4, EPO-R and NGF-R.
PLoS One. 2014; 9(1):e84417 [PubMed] Free Access to Full Article Related Publications
Malignant melanoma is a life-threatening skin cancer increasingly diagnosed in the western world. In advanced disease the prognosis is grave. Growth and metastasis formation in melanomas are regulated by a network of cytokines, cytokine-receptors, and adhesion molecules. However, little is known about surface antigens and target expression profiles in human melanomas. We examined the cell surface antigen profile of human skin melanoma cells by multicolor flow cytometry, and compared their phenotype with 4 melanoma cell lines (A375, 607B, Mel-Juso, SK-Mel28). Melanoma cells were defined as CD45-/CD31- cells co-expressing one or more melanoma-related antigens (CD63, CD146, CD166). In most patients, melanoma cells exhibited ErbB3/Her3, CD44/Pgp-1, ICAM-1/CD54 and IGF-1-R/CD221, but did not express CD20, ErbB2/Her2, KIT/CD117, AC133/CD133 or MDR-1/CD243. Melanoma cell lines were found to display a similar phenotype. In most patients, a distinct subpopulation of melanoma cells (4-40%) expressed the erythropoietin receptor (EPO-R) and ErbB4 together with PD-1 and NGF-R/CD271. Both the EPO-R+ and EPO-R- subpopulations produced melanoma lesions in NOD/SCID IL-2Rgamma(null) (NSG) mice in first and secondary recipients. Normal skin melanocytes did not express ErbB4 or EPO-R, but expressed a functional KIT receptor (CD117) as well as NGF-R, ErbB3/Her3, IGF-1-R and CD44. In conclusion, melanoma cells display a unique composition of surface target antigens and cytokine receptors. Malignant transformation of melanomas is accompanied by loss of KIT and acquisition of EPO-R and ErbB4, both of which are co-expressed with NGF-R and PD-1 in distinct subfractions of melanoma cells. However, expression of EPO-R/ErbB4/PD-1 is not indicative of a selective melanoma-initiating potential.

Related: Melanoma Skin Cancer PDCD1

Zhang M, Yang Q, Zhang L, et al.
miR-302b is a potential molecular marker of esophageal squamous cell carcinoma and functions as a tumor suppressor by targeting ErbB4.
J Exp Clin Cancer Res. 2014; 33:10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ErbB4 expression has been noted in various tumors, but its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to investigate whether miR-302b regulates the expression of ErbB4 at the post-transcriptional level and to determine its expression, significance, and function in ESCC.
METHODS: We used real-time reverse transcriptase-polymerase chain reaction to quantify the expression of miR-302b in 50 ESCC tissues and analyzed its relationship with clinicopathological factors and survival. Then, we investigated the post-transcriptional regulation of ErbB4 expression using immunoblot analysis and luciferase reporter assays. Finally, the effects of miR-302b on proliferation, apoptosis, and invasion of ESCC cells was detected using MTT, flow cytometric analysis, and transwell invasion assays, respectively.
RESULTS: miR-302b was significantly down-regulated and correlated with tumor differentiation and lymph node metastasis in ESCC. Univariate and multivariate analyses indicated that low miR-302b expression might be a poor prognostic factor. Further studies demonstrated that miR-302b post-transcriptionally down-regulated the expression of ErbB4 in vitro. Moreover, miR-302b inhibited proliferation by inducing apoptosis and repressed invasion in the ESCC cell lines.
CONCLUSIONS: miR-302b is a potential molecular marker of ESCC and functions as a tumor suppressor by post-transcriptionally regulating ErbB4.

Related: Cancer of the Esophagus Esophageal Cancer

Ribeiro IP, Marques F, Caramelo F, et al.
Genetic gains and losses in oral squamous cell carcinoma: impact on clinical management.
Cell Oncol (Dordr). 2014; 37(1):29-39 [PubMed] Related Publications
PURPOSE: The identification of genetic markers associated with oral cancer is considered essential to improve the diagnosis, prognosis, early tumor and relapse detection and, ultimately, to delineate individualized therapeutic approaches. Here, we aimed at identifying such markers.
METHODS: Multiplex Ligation-dependent Probe Amplification (MLPA) analyses encompassing 133 cancer-related genes were performed on a panel of primary oral tumor samples and its corresponding resection margins (macroscopically tumor-free tissue) allowing, in both types of tissue, the detection of a wide arrange of copy number imbalances on various human chromosomes.
RESULTS: We found that in tumor tissue, from the 133 cancer-related genes included in this study, those that most frequently exhibited copy number gains were located on chromosomal arms 3q, 6p, 8q, 11q, 16p, 16q, 17p, 17q and 19q, whereas those most frequently exhibiting copy number losses were located on chromosomal arms 2q, 3p, 4q, 5q, 8p, 9p, 11q and 18q. Several imbalances were highlighted, i.e., losses of ERBB4, CTNNB1, NFKB1, IL2, IL12B, TUSC3, CDKN2A, CASP1, and gains of MME, BCL6, VEGF, PTK2, PTP4A3, RNF139, CCND1, FGF3, CTTN, MVP, CDH1, BRCA1, CDKN2D, BAX, as well as exon 4 of TP53. Comparisons between tumor and matched macroscopically tumor-free tissues allowed us to build a logistic regression model to predict the tissue type (benign versus malignant). In this model, the TUSC3 gene showed statistical significance, indicating that loss of this gene may serve as a good indicator of malignancy.
CONCLUSIONS: Our results point towards relevance of the above mentioned cancer-related genes as putative genetic markers for oral cancer. For practical clinical purposes, these genetic markers should be validated in additional studies.

Related: Oral Cancer

Silva SD, Alaoui-Jamali MA, Hier M, et al.
Cooverexpression of ERBB1 and ERBB4 receptors predicts poor clinical outcome in pN+ oral squamous cell carcinoma with extranodal spread.
Clin Exp Metastasis. 2014; 31(3):307-16 [PubMed] Related Publications
Overexpression of members of the ErbB receptor family is common in oral squamous cell carcinomas (OSCC); however, their prognostic value for aggressive OSCC has been debated. Extranodal spread to cervical lymph nodes is the most significant prognostic indicator in OSCC. In the present study, we investigated the clinical significance of single versus paired overexpression of members of the ErbB receptor family in 82 OSCC patients with lymph nodes metastasis, with or without capsular rupture (CR) followed by at least 10 years. Immunohistochemistry analysis revealed a common overexpression of ErbB1 (P = 0.021), ErbB2 (P = 0.001), ErbB4 (P = 0.048), as well as MMP-2 (P = 0.043) in OSCC cases with CR+. Increased expression of ErbB1 was associated with MMP-2 in tumors with advanced clinical stages, including poorly differentiated (grade III) tumors (P < 0.050). Vascular embolization was associated with MMP-2 (P = 0.021) and MMP-13 (P = 0.010) overexpression. Survival analysis revealed a lower survival probability in tumors overexpressing ErbB1 (P = 0.038), ErbB4 (P = 0.043), and MMP-12 (P = 0.050). As well a strong association was observed in cases with high risk of recurrence and strong immunostaining for ErbB1 (P = 0.017), ErbB4 (P = 0.008), MMP-1 (P = 0.003), MMP-2 (P = 0.016), MMP-10 (P = 0.041), and MMP-13 (P = 0.005). Stratified multivariate survival analysis revealed a strong prognostic interdependence of ErbB1 and ErbB4 cooverexpression in predicting the worst overall and disease-free survivals (P = 0.0013 and P = 0.0004, respectively). Taken together, these results support a cooperation of ErbB1, ErbB4, and members of the MMP family in predicting OSCC invasion and poor clinical outcomes.

Related: MMP2 Oral Cancer

Han W, Jones FE
HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation.
Biochem Biophys Res Commun. 2014; 443(2):458-63 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
The EGFR-family member HER4 undergoes regulated intramembrane proteolysis (RIP) to generate an intracellular domain (4ICD) that functions as a transcriptional coactivator. Accordingly, 4ICD coactivates the estrogen receptor (ER) and associates with ER at target gene promoters in breast tumor cells. However, the extent of 4ICD coactivation of ER and the functional significance of the 4ICD/ER transcriptional complex is unclear. To identify 4ICD coactivated genes we performed a microarray gene expression analysis of β-estradiol treated cells comparing control MCF-7 breast cancer cells to MCF-7 cells where HER4 expression was stably suppressed using a shRNA. In the MCF-7 cell line, β-estradiol significantly stimulated or repressed by 2-fold or more 726 or 53 genes, respectively. Significantly, HER4/4ICD was an obligate coactivator for 277 or 38% of the β-estradiol stimulated genes. Ingenuity Pathway Analysis of β-estradiol regulated genes identified significant associations with multiple cellular functions regulating cellular growth and proliferation, cell cycle progression, cancer metastasis, decreased hypoplasia, tumor cell migration, apoptotic resistance of tumor cells, and increased transcription. Genes coactivated by 4ICD displayed functional specificity by only significantly contributing to cellular growth and proliferation, cell cycle progression, and decreased hypoplasia. In direct concordance with these in situ results we show that HER4 knockdown in MCF-7 cells results in a loss of estrogen stimulated tumor cell proliferation and cell cycle progression, whereas, estrogen stimulated tumor cell migration was unaffected by loss of HER4 expression. In summary, we demonstrate for the first time that a cell surface receptor functions as an obligate ER coactivator with functional specificity associated with breast tumor cell proliferation and cell cycle progression. Nearly 90% of ER positive tumors coexpress HER4, therefore we predict that the majority of breast cancer patients would benefit from a strategy to therapeutic disengage ER/4ICD coregulated tumor cell proliferation.

Related: Breast Cancer

Lau C, Killian KJ, Samuels Y, Rudloff U
ERBB4 mutation analysis: emerging molecular target for melanoma treatment.
Methods Mol Biol. 2014; 1102:461-80 [PubMed] Related Publications
Recent sequencing efforts in melanoma have elucidated many previously unknown molecular pathways and biological mechanisms involved in melanoma development and progression and have yielded a number of promising targets for molecular therapy. As sequencing technologies have become more sophisticated and have revealed an ever-increasing complexity of the genetic landscape of melanoma, it has become clear that sequencing methods applied to clinical specimens have to reliably capture not only recurrent "hotspot" mutations like BRAFV600 and NRASQ61 or "mini-hotspot" mutations like exon 11 and 13 c-KIT but also heterogeneous somatic mutations dispersed across multiple functionally conserved regions of genes or entire genes. One such example in melanoma is the ERBB4 receptor, or HER4, a member of the Erb receptor family, which has recently been shown to be a major oncogenic "driver" in melanoma. Mutated ERBB4 signaling activates both aberrant ERBB4 and PI3K-AKT signal transduction, mediates sensitivity to small-molecule inhibition with the dual-tyrosine kinase inhibitor lapatinib, and has recently also been implied in oncogenic glutamatergic signaling in melanoma. Mutations involving the ERBB4 gene act as "gain-of-function" mutations and predominantly involve the extracellular domains of the receptor. Additional sequencing efforts have recently identified recurrent mutations ("mini-hotspots") or mutation clusters which affect the regulation of, e.g., ligand binding, arrangement of extracellular domain alignment, or intramolecular tether formation.In this chapter, we describe the methods used to determine the mutation status of all exons of the ERBB4 gene in clinical specimens obtained from patients afflicted by metastatic melanoma. Upon slight modifications, this protocol can also be used for mutational analysis of other oncogenes affected by "non-hotspot" mutations dispersed across multiple exons. This sequencing technique has successfully been applied within a clinical trial selecting patients with ERBB4-mutant melanoma for lapatinib treatment. With the increasing emergence of low-frequency oncogenes affected by heterogeneous activating mutations located in different exons and regions this method will provide a mean to translate the promise of recently obtained genetic knowledge into clinical genotype-directed targeted therapy trials.

Related: Melanoma

Machleidt A, Buchholz S, Diermeier-Daucher S, et al.
The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients.
BMC Cancer. 2013; 13:437 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
BACKGROUND: Not only four but rather seven different human epidermal growth factor receptor related (Her) receptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues: Her1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms does not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer patients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear.
METHODS: We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific polymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign breast tissues.
RESULTS: In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In contrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios. We identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in Her2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In Her2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in ER-negative individuals.
CONCLUSION: In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously expressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of the two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged EFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms, into account might render more precisely the molecular diagnostics required for the development of optimized targeted therapies.

Related: Breast Cancer

Flågeng MH, Knappskog S, Haynes BP, et al.
Inverse regulation of EGFR/HER1 and HER2-4 in normal and malignant human breast tissue.
PLoS One. 2013; 8(8):e74618 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
Cross-talk between the estrogen and the EGFR/HER signalling pathways has been suggested as a potential cause of resistance to endocrine therapy in breast cancer. Here, we determined HER1-4 receptor and neuregulin-1 (NRG1) ligand mRNA expression levels in breast cancers and corresponding normal breast tissue from patients previously characterized for plasma and tissue estrogen levels. In tumours from postmenopausal women harbouring normal HER2 gene copy numbers, we found HER2 and HER4, but HER3 levels in particular, to be elevated (2.48, 1.30 and 22.27 -fold respectively; P<0.01 for each) compared to normal tissue. Interestingly, HER3 as well as HER4 were higher among ER+ as compared to ER- tumours (P=0.004 and P=0.024, respectively). HER2 and HER3 expression levels correlated positively with ER mRNA (ESR1) expression levels (r=0.525, P=0.044; r=0.707, P=0.003, respectively). In contrast, EGFR/HER1 was downregulated in tumour compared to normal tissue (0.13-fold, P<0.001). In addition, EGFR/HER1 correlated negatively to intra-tumour (r=-0.633, P=0.001) as well as normal tissue (r=-0.556, P=0.006) and plasma estradiol levels (r=-0.625, P=0.002), suggesting an inverse regulation between estradiol and EGFR/HER1 levels. In ER+ tumours from postmenopausal women, NRG1 levels correlated positively with EGFR/HER1 (r=0.606, P=0.002) and negatively to ESR1 (r=-0.769, P=0.003) and E2 levels (r=-0.542, P=0.020). Our results indicate influence of estradiol on the expression of multiple components of the HER system in tumours not amplified for HER2, adding further support to the hypothesis that cross-talk between these systems may be of importance to breast cancer growth in vivo.

Related: Breast Cancer ERBB2 (HER2) ERBB3

Kunz M
New developments in dermatological oncogenetics.
J Dtsch Dermatol Ges. 2013; 11(9):831-6 [PubMed] Related Publications
Activated intracellular signaling pathways based on mutations in oncogenes and tumor suppressor genes play an important role in a variety of malignant tumors. In dermatology, such mutations have been identified in melanoma, basal cell carcinoma and squamous cell carcinoma. These have partly led to the establishment of new, targeted therapies. Treatment successes have been particularly impressive for melanoma with small molecule inhibitors directed against the mutated BRAF oncogene and in basal cell carcinoma with inhibitors directed against the hedgehog signaling pathway. New sequencing technologies, in particular next generation sequencing, have led to a better and more comprehensive understanding of malignant tumors. This approach confirmed the pathogenic role of BRAF, NRAS and MAP kinase pathways for melanoma. At the same time, a series of further interesting target molecules with oncogenic mutations such as ERBB4, GRIN2A, GRM3, PREX2, RAC1 and TP53 were identified. New aspects have recently been shown for squamous cell carcinoma by detection of mutations in the NOTCH signaling pathway. A better understanding of the pathogenesis of these and other tumors should lead to improved and maybe even individualized treatment. The current developments in dermatological oncogenetics based on the new sequencing technologies are reviewed.

Related: Skin Cancer

Ma D, Hovey RL, Zhang Z, et al.
Genetic variations in EGFR and ERBB4 increase susceptibility to cervical cancer.
Gynecol Oncol. 2013; 131(2):445-50 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
OBJECTIVES: Inherited genetic variability contributes to susceptibility to cervical cancer. We investigated the association of single nucleotide polymorphisms (SNPs) in the human epidermal growth factor receptor (ERBB) family with cervical cancer.
METHODS: We used the transmission disequilibrium test (TDT) to look for excessive transmission of tag single nucleotide polymorphisms (tSNPs) in ERBB family members EGFR, ERBB2, ERBB3, and ERBB4 in a large sample of women with invasive and in situ cervical cancer and their biological parents (628 trios). The study used a discovery set of trios (244) analyzed by Illumina GoldenGate in which SNPs reaching a P<.05 were re-tested by TaqMan in the combined set of 628. We also explored collaborative effects of different ERBB alleles.
RESULTS: Based on single SNP TDT tests we identified 16 significant SNPs in the discover stage and six of 14 SNPs that could be assayed by TaqMan were significantly overtransmitted in women with cervical cancer in the combined replication set. Four SNPs were located in intron 1 of EGFR and two SNPs in intron 24 of ERBB4. The EGFR variants are located near multiple enhancers, silencers, and the previously identified functional common polymorphisms in intron 1.
CONCLUSIONS: Our data provide evidence for the involvement of intron 1 EGFR variants and intron 24 ERBB4 variants in modulating risk for the development of in situ and invasive cervical cancer. These variants should be examined in additional populations and functional studies would be needed to confirm this hypothesis.

Related: Cervical Cancer EGFR

Guo WG, Zhang Y, Ge D, et al.
Bioinformatics analyses combined microarray identify the desregulated microRNAs in lung cancer.
Eur Rev Med Pharmacol Sci. 2013; 17(11):1509-16 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) play an important role in the regulation of cell growth, differentiation, apoptosis, and carcinogenesis. Deregulated miRNAs are found in blood cells of cancer patients recently.
AIM: This study aims to screen the differentially expressed miRNAs (DE-miRNAs) which could discriminate lung cancers from non-cancerous lung tissues as well as molecular signatures that differ in tumor histology.
MATERIALS AND METHODS: miRNA expression profiles of GSE17681 was downloaded from Gene Expression Omnibus database. Three test methods were used to identify DE-miRNAs between lung cancer tissue and healthy controls. Target genes of DE-miRNAs were retrieved from three databases and mapped to KEGG to investigate their roles in lung cancer. Further, a protein-protein interaction (PPI) network was constructed used STRING and Cytoscape.
RESULTS: A total of 17 DE-miRNAs were identified. Among them, hsa-miR-339-5p draw specific attention. Pathway analysis revealed that target genes of RASSF1 and KRAS play roles as oncogene or tumor suppressor gene in the progression of lung cancer. Besides, Target genes of RASSF1 and ERBB4 formed a module in the PPI network. Functional analysis suggested biological process of response to hypoxia was significantly enriched.
CONCLUSIONS: hsa-miR-339-5p play important role in the regulation of lung cancer and it may be potential to be used as biomarker to predict lung cancer progression.

Related: Lung Cancer RASSF1

Mendoza-Naranjo A, El-Naggar A, Wai DH, et al.
ERBB4 confers metastatic capacity in Ewing sarcoma.
EMBO Mol Med. 2013; 5(7):1019-34 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES.

Related: Bone Cancers AKT1 Ewing's Sarcoma Signal Transduction

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Related: Signal Transduction Stomach Cancer Gastric Cancer

Chen X, Zhu Q, Zhu L, et al.
Clinical perspective of afatinib in non-small cell lung cancer.
Lung Cancer. 2013; 81(2):155-61 [PubMed] Related Publications
Reversible ATP-competitive inhibitors targeting the epidermal growth factor receptor (EGFR) have been established as the most effective treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring "activating" mutations in exons 19 and 21 of the EGFR gene. However, clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment. The mechanisms for acquired resistance include selection of the EGFR T790M mutation in approximately 50% of cases, and MET gene amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms. Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. In preclinical studies, afatinib not only inhibited the growth of models with common activating EGFR mutations, but was also active in lung cancer models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program. These trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib. Here we review the current status of clinical application of afatinib in NSCLC. We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention.

Related: Non-Small Cell Lung Cancer Lung Cancer

Hu YL, Zhong D, Pang F, et al.
HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes.
Genet Mol Res. 2013; 12(2):1327-35 [PubMed] Related Publications
Prostate cancer is one of the most commonly diagnosed male malignancies. Genome wide association studies have revealed HNF1b to be a major risk gene for prostate cancer susceptibility. We examined the mechanisms of involvement of HNF1b in prostate cancer development. We integrated data from Gene Expression Omnibus prostate cancer genes from the Dragon Database of Genes Implicated in Prostate Cancer, and used meta-analysis data to generate a panel of HNF1b-associated prostate cancer risk genes. An RT-PCR was used to assess expression levels in DU145, PC3, LNCaP, and RWEP-1 cells. Twelve genes (BAG1, DDR1, ERBB4, ESR1, HSPD1, IGFBP2, IGFBP5, NR4A1, PAWR, PIK3CG, RAP2A, and TPD52) were found to be associated with both HNF1b and prostate cancer risk. Six of them (BAG1, ERBB4, ESR1, HSPD1, NR4A1, and PIK3CG) were mapped to the KEGG pathway, and submitted to further gene expression assessment. HNF1b, NR4A1, and HSPD1 were found to be highly expressed in the LNCaP androgenic hormone-dependent cell line. Compared to expression levels in wild-type prostate cancer cells, NR4A1, HSPD1, ERBB4, and ESR1 expression levels were also found to be significantly increased in the HNF1b-transfected cells. We conclude that the mechanism of action of HNF1b in prostate cancer involves modulation of the association between androgenic hormone and prostate cancer cells. Gene-gene interaction and coordination should be taken into account to determine relationships between specific loci and diseases.

Related: Prostate Cancer Signal Transduction HNF1B

Nakano H, Yamada Y, Miyazawa T, Yoshida T
Gain-of-function microRNA screens identify miR-193a regulating proliferation and apoptosis in epithelial ovarian cancer cells.
Int J Oncol. 2013; 42(6):1875-82 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
MicroRNAs (miRNAs) are a small class of non‑coding RNAs that negatively regulate gene expression, and are considered as new therapeutic targets for treating cancer. In this study, we performed a gain-of-function screen using miRNA mimic library (319 miRNA species) to identify those affecting cell proliferation in human epithelial ovarian cancer cells (A2780). We discovered a number of miRNAs that increased or decreased the cell viability of A2780 cells. Pro-proliferative and anti-proliferative miRNAs include oncogenic miR-372 and miR-373, and tumor suppressive miR-124a, miR-7, miR-192 and miR-193a, respectively. We found that overexpression of miR-124a, miR-192, miR-193a and miR‑193b inhibited BrdU incorporation in A2780 cells, indicating that these miRNAs affected the cell cycle. Overexpression of miR‑193a and miR-193b induced an activation of caspase 3/7, and resulted in apoptotic cell death in A2780 cells. A genome‑wide gene expression analysis with miR-193a-transfected A2780 cells led to identification of ARHGAP19, CCND1, ERBB4, KRAS and MCL1 as potential miR-193a targets. We demonstrated that miR-193a decreased the amount of MCL1 protein by binding 3'UTR of its mRNA. Our study suggests the potential of miRNA screens to discover miRNAs as therapeutic tools to treat ovarian cancer.

Related: Apoptosis Ovarian Cancer BCL1 Gene (CCND1) KRAS gene MCL1

Kobayashi H, Kumagai K, Gotoh A, et al.
Upregulation of epidermal growth factor receptor 4 in oral leukoplakia.
Int J Oral Sci. 2013; 5(1):14-20 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP.

Related: ERBB3 TGFA

Caltabiano R, Barbagallo GM, Castaing M, et al.
Prognostic value of EGFR expression in de novo and progressed atypical and anaplastic meningiomas: an immunohistochemical and fluorescence in situ hybridization pilot study.
J Neurosurg Sci. 2013; 57(2):139-51 [PubMed] Related Publications
AIM: The aim of this study was to assess both the epidermal growth factor receptor (EGFR) protein expression by immunohistochemistry and the EGFR gene amplification by fluorescence in situ hybridization in meningiomas of different grade, in order to evaluate their possible role in the development of the disease. EGFR protein belongs to the family of tyrosine kinase growth factor receptors, which also includes HER2, HER3 and HER4. Elevated expression or activity of EGFR has been reported in several cancers, including brain tumours. EGFR activation can enhance the malignant potential of epithelial tissues.
METHODS: We investigated whether there was a difference in the EGFR protein expression and the EGFR gene amplification between the so called de novo malignant meningiomas and recurrent meningiomas with or without malignant progression from a previously lower grade tumor. Our goal was to evaluate if EGFR expression was a useful marker to select patients affected by meningioma with a major risk of recurrences. We also assessed the prognostic value of the EGFR expression on overall survival.
RESULTS: Progression from benign meningiomas to atypical or anaplastic meningiomas correlated with an increase in the expression of EGFR protein. Our study shows that EGFR immunostaining in meningiomas directly correlates to the tumor's grade. The EGFR expression did not correlate with the overall survival and the recurrence-free survival of the patients affected by meningioma (de novo, recurrent and progressed).
CONCLUSION: We submit that the EGFR expression is not a useful prognostic element to identify patients with a major risk of meningioma recurrence.

Related: FISH EGFR

Zhang K, Wong P, Duan J, et al.
An ERBB3/ERBB2 oncogenic unit plays a key role in NRG1 signaling and melanoma cell growth and survival.
Pigment Cell Melanoma Res. 2013; 26(3):408-14 [PubMed] Related Publications
We recently identified neuregulin-1 (NRG1) as a novel target of Notch1 required in Notch-dependent melanoma growth. ERBB3 and ERBB4, tyrosine kinase receptors specifically activated by NRG1, have been shown to be either elevated in melanoma cell lines and tumors or to be mutated in 20% of melanomas, respectively. While these data support key roles of NRG1 and its receptors in the pathogenesis of melanoma, whether ERBB3 and ERBB4 display redundant or exclusive functions is not known. Here, we show that ERBB3 and ERBB4 inhibition results in distinct outcomes. ERBB3 inhibition ablates the cellular responses to NRG1, results in AKT inactivation and leads to cell growth arrest and apoptotic cell death. In contrast, ERBB4 knockdown mildly affects cell growth, has no effects on cell survival and, importantly, does not alter the responses to NRG1. Finally, we identified ERBB2 as a key coreceptor in NRG1-dependent ERBB3 signaling. ERBB2 forms a complex with ERBB3, and its inhibition recapitulates the phenotypes observed upon ERBB3 ablation. We propose that an NRG1-ERBB3-ERBB2 signaling unit operates in melanoma cells where it promotes growth and survival.

Related: Melanoma AKT1 ERBB3 Signal Transduction

Wu Y, Zhang Y, Wang M, et al.
Downregulation of HER3 by a novel antisense oligonucleotide, EZN-3920, improves the antitumor activity of EGFR and HER2 tyrosine kinase inhibitors in animal models.
Mol Cancer Ther. 2013; 12(4):427-37 [PubMed] Related Publications
Among the four human EGF receptor (HER) family members (EGFR, HER2, HER3, HER4), HER3 is of particular interest as it interacts with HER2 and EGFR via heterodimerization and is a key link to the phosphoinositide 3-kinase (PI3K)/AKT signal transduction axis. Recent studies indicate that HER3 plays a critical role in mediating resistance to agents that target EGFR or HER2. As HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. We describe here a locked nucleic acid (LNA)-based HER3 antisense oligonucleotide, EZN-3920, that specifically downmodulated the expression of HER3, which was associated with growth inhibition. EZN-3920 effectively downmodulated HER3 expression, HER3-driven PI3K/AKT signaling pathway, and growth in tumors derived from BT474M1 breast and HCC827 lung carcinoma cell lines, which overexpress HER2 and EGFR, respectively. Furthermore, when EZN-3920 was coadministered with gefitinib or lapatinib in xenograft tumor models, enhanced antitumor activity compared with the effect of monotherapy was found. The effect was associated with a blockade of induced HER3 mRNA expression caused by lapatinib or gefitinib treatment. Finally, EZN-3920 sustained its antiproliferative effect in trastuzumab-resistant cells and three independently derived gefitinib-resistant cells. Our findings show that downmodulation of HER3 by EZN-3920 leads to the suppression of tumor growth in vitro and in vivo, suggesting that HER3 can be an effective target for the treatment of various cancers that have been activated by HER3 alone or where HER3 activation is associated with EGFR or HER2 expression.

Related: Breast Cancer ERBB3

Gunes S, Sullu Y, Yegin Z, et al.
ErbB receptor tyrosine kinase family expression levels in urothelial bladder carcinoma.
Pathol Res Pract. 2013; 209(2):99-104 [PubMed] Related Publications
ErbB receptor tyrosine kinases family plays an important role in cell cycle regulation. Overexpression of ErbB receptors has been described in several solid tumors. The aim of this study was to investigate the levels of ErbB1, ErbB2, ErbB3, and ErbB4 expression in bladder cancer. Urinary bladder tumor samples were obtained from 33 bladder cancers and 7 non-cancerous bladder biopsies. The levels of ErbB1, ErbB2, ErbB3, and ErbB4 genes expression in bladder cancer were determined by real-time PCR. The presence of protein was confirmed by immunostaining. Expression of ErbB1, ErbB2, ErbB3, and ErbB4 genes increased 0.67, 4.72, 2.89, and 2.65-fold, respectively, in bladder tumors as compared with normal tissue. There was a significant difference between immunostaining results of ErbB4 protein in bladder tumors and normal bladder tissue (P<0.01). The present data suggest that ErbB2, ErbB3, and ErbB4 genes may have a role in bladder cancer tumorigenesis.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology

Jung IH, Leem GL, Jung DE, et al.
Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish.
Neuro Oncol. 2013; 15(3):290-304 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
BACKGROUND: Ongoing characterization of glioma has revealed that Akt signaling plays a crucial role in gliomagenesis. In mouse models, however, Akt alone was not sufficient to induce glioma.
METHODS: We established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1(G12V) (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.
RESULTS: Transgene expressions were spatiotemporally restricted without any developmental abnormality of embryos and persisted at cerebellum and medulla in adult zebrafish. DAAkt1 alone induced glioma (with visible bumps at the head), with incidences of 36.6% and 49% at 6 and 9 months, respectively. Histologically, gliomas showed various histologic grades, increased proliferation, and frequent invasion into the fourth ventricle. Preferential location of small tumors at periventricular area and coexpression of Her4 suggested that tumors originated from Ptf1a- and Her4-positive progenitor cells at ventricular zone. Gliomagenesis was principally mediated by activation of survival pathway through upregulation of survivin genes. Although DARac1 alone was incapable of gliomagenesis, when coexpressed with DAAkt1, gliomagenesis was accelerated, showing higher tumor incidences (62.0% and 73.3% at 6 and 9 months, respectively), advanced histologic grade, invasiveness, and shortened survival. DARac1 upregulated survivin2, cyclin D1, β-catenin, and snail1a but downregulated E-cadherin, indicating that DARac1 promotes gliomagenesis by enhancing proliferation, survival, and epithelial-to-mesenchymal transition. On pharmacologic tests, only Akt1/2 inhibitor effectively suppressed gliomagenesis, inhibited cellular proliferation, and induced apoptosis in established gliomas.
CONCLUSIONS: The zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.

Related: AKT1 Signal Transduction

Oikawa M, Miki Y, Shimizu Y, Kumamoto H
Assessment of protein expression and gene status of human epidermal growth factor receptor (HER) family molecules in ameloblastomas.
J Oral Pathol Med. 2013; 42(5):424-34 [PubMed] Related Publications
BACKGROUND: To evaluate roles of human epidermal growth factor receptor (HER) family molecules in ameloblastomas, protein expression and gene status were analyzed in odontogenic tissues.
METHODS: Sixty five ameloblastomas, 10 dental follicles, and 11 dentigerous cysts were immunohistochemically examined with antibodies against epidermal growth factor receptor (EGFR) and HER2, HER3, and HER4. Amplification of EGFR and HER2 was evaluated by chromogenic in situ hybridization (CISH). In 18 ameloblastomas, EGFR exons 19 and 21 were analyzed by direct DNA sequencing.
RESULTS: Immunohistochemical reactivity for EGFR and HER2, HER3, and HER4 was detected in odontogenic epithelium. Expression of EGFR and HER4 was remarkable in these odontogenic tissues, as compared with that of HER2 and HER3. The level of HER2 immunoreactivity was significantly lower in ameloblastomas than in dental follicles and dentigerous cysts. Follicular ameloblastomas showed significantly higher expression of HER2 and HER4 than plexiform ameloblastomas. Reactivity for EGFR and HER3 was slightly stronger in recurrent ameloblastomas than in primary ameloblastomas. CISH did not reveal obvious amplification of EGFR or HER2 in ameloblastomas; however, EGFR and HER2 gene signals were significantly higher in follicular ameloblastomas than in plexiform ameloblastomas. Direct DNA sequencing of EGFR did not show any gene alteration in ameloblastomas.
CONCLUSION: Expression of HER family molecules, especially EGFR and HER4, in odontogenic tissues suggests that growth signals mediated by these receptor molecules contribute to cell proliferation, survival, and differentiation in both normal and neoplastic odontogenic epithelial tissues. Some of these molecules might be useful for predicting outcomes in patients with ameloblastomas.

Related: ERBB3

Lassaletta L, Torres-Martín M, San-Román-Montero J, et al.
DNA copy gains of tumor-related genes in vestibular schwannoma.
Eur Arch Otorhinolaryngol. 2013; 270(9):2433-8 [PubMed] Related Publications
DNA copy gains are a common event in tumor growth. This study determines the gene dosage/amplification of seven tumor-related genes in patients undergoing vestibular schwannoma (VS) surgery and analyzes its clinical implications. Thirty-three patients undergoing surgery for VS were studied. Seven genes (EGFR, ERBB2, ERBB3, ERBB4, MDM2, MDM4, and NMYC) were analyzed by Quantitative real-time PCR. Copy gains were correlated with demographic, clinical and radiological data. Of the 33 samples, 48 % were positive for copy gains in at least one gene. There were no positive samples for gene amplification. A clinical correlation between tumor size and copy gains of ERBB2 was found. Patients with copy gains of this gene had larger tumors measured by diameter (p = 0.027) and volume (p = 0.005). Copy gains of EGFR, ERBB2, ERBB4, and MDM4 were associated with preoperative tinnitus. Contrary to other tumors of the central nervous system, development of VS does not appear to involve gene amplification. However, copy gains of certain tumor-related genes may play a role in the biological behavior of these neoplasms. Our findings support the role of ERBB2 in VS development and growth.

Related: ERBB2 (HER2) Acoustic Neuroma

MacLeod SH, Elgadi MM, Bossi G, et al.
HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice.
Cancer Gene Ther. 2012; 19(12):888-98 [PubMed] Related Publications
Despite the tremendous potential of adenovirus (Ad) as a delivery vector for cancer gene therapy, its use in clinical settings has been limited, mainly as a result of the limited infectivity in many tumors and the wide tissue tropism associated with Ad. To modify the tropism of the virus, we have inserted the epidermal growth factor-like domain of the human heregulin-α (HRG) into the HI loop of Ad5 fiber. This insertion had no adverse effect on fiber trimerization nor did it affect incorporation of the modified fiber into infectious viral particles. Virions bearing modified fiber displayed growth characteristics and viral yields indistinguishable from those of wild-type (wt) virus. Most importantly, HRG-tagged virions showed enhanced infection of cells expressing the cognate receptors HER3/ErbB3 and HER4/ErbB4. This was significantly reduced in the presence of soluble HRG. Furthermore, HER3-expressing Chinese hamster ovary (CHO) cells were transduced by the HRG-modified virus, but not by wt virus. In contrast, CHO cells expressing the coxsackie-Ad receptor were transduced with both viruses. However, infection of an in vivo breast cancer xenograft model after intratumoral injection was similar with both viruses, suggesting that the tumor microenvironment and/or the route of delivery have important roles in infection of target cells with fiber-modified Ads.

Related: Breast Cancer ERBB3

Imbert AM, Garulli C, Choquet E, et al.
CD146 expression in human breast cancer cell lines induces phenotypic and functional changes observed in Epithelial to Mesenchymal Transition.
PLoS One. 2012; 7(8):e43752 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
BACKGROUND: Metastasis is an important step in tumor progression leading to a disseminated and often incurable disease. First steps of metastasis include down-regulation of cell adhesion molecules, alteration of cell polarity and reorganization of cytoskeleton, modifications associated with enhanced migratory properties and resistance of tumor cells to anoikis. Such modifications resemble Epithelial to Mesenchymal Transition (EMT). In breast cancer CD146 expression is associated with poor prognosis and enhanced motility.
METHODOLOGY/PRINCIPAL FINDINGS: On 4 different human breast cancer cell lines, we modified CD146 expression either with shRNA technology in CD146 positive cells or with stable transfection of CD146 in negative cells. Modifications in morphology, growth and migration were evaluated. Using Q-RT-PCR, we analyzed the expression of different EMT markers. We demonstrate that high levels of CD146 are associated with loss of cell-cell contacts, expression of EMT markers, increased cell motility and increased resistance to doxorubicin or docetaxel. Experimental modulation of CD146 expression induces changes consistent with the above described characteristics: morphology, motility, growth in anchorage independent conditions and Slug mRNA variations are strictly correlated with CD146 expression. These changes are associated with modifications of ER (estrogen receptor) and Erb receptors and are enhanced by simultaneous and opposite modulation of JAM-A, or exposure to heregulin, an erb-B4 ligand.
CONCLUSIONS: CD146 expression is associated with an EMT phenotype. Several molecules are affected by CD146 expression: direct or indirect signaling contributes to EMT by increasing Slug expression. CD146 may also interact with Erb signaling by modifying cell surface expression of ErbB3 and ErbB4 and increased resistance to chemotherapy. Antagonistic effects of JAM-A, a tight junction-associated protein, on CD146 promigratory effects underline the complexity of the adhesion molecules network in tumor cell migration and metastasis.

Related: Breast Cancer

Płuciennik E, Nowakowska M, Wujcicka WI, et al.
Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis.
Oncol Rep. 2012; 28(4):1417-22 [PubMed] Related Publications
Loss of heterozygosity (LOH) in 16q appears in ~20-30% cases of Wilms' tumor. Within this region, known as common fragile site FRA16D, the WWOX tumor suppressor gene is located. Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis. The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms' tumor samples. We evaluated the correlation between expression of WWOX and genes involved in proliferation (Ki67), apoptosis (BCL2, BAX), signal transduction (ERBB4, ERBB2, EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription (TP73) using real-time RT-PCR in 23 tumor samples. We also analyzed the potential causes of WWOX gene expression reduction i.e., promoter methylation status (MethylScreen method) and loss of heterozygosity (LOH) status. We revealed a positive correlation between WWOX expression and BCL2, BCL2/BAX ratio, EGFR, ERBB4 isoform JM-a, TP73 and negative correlation with both cyclins. Loss of heterozygosity of the WWOX gene was observed only at intron 8, however, it had no influence on the reduction of its expression levels. Contrary to LOH, methylation of the region covering the 3' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels. In the present study we reveal that in Wilms' tumors the WWOX expression levels are positively associated with the process of apoptosis, signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle (by cyclin E1 and D1). Moreover, our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation.

Related: Apoptosis MKI67 Kidney Cancer Signal Transduction Wilms' Tumour Wilms Tumour BCL1 Gene (CCND1)


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Cite this page: Cotterill SJ. ERBB4 (HER4), Cancer Genetics Web: http://www.cancerindex.org/geneweb/ERBB4.htm Accessed: date

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