FGF4

Gene Summary

Gene:FGF4; fibroblast growth factor 4
Aliases: HST, KFGF, HST-1, HSTF1, K-FGF, HBGF-4
Location:11q13.3
Summary:The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:fibroblast growth factor 4
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: FGF4 (cancer-related)

Yasuda K, Torigoe T, Mariya T, et al.
Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity.
Lab Invest. 2014; 94(12):1355-69 [PubMed] Related Publications
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1(high)) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1(high) cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1(high) cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1(high) cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1(high) cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1(high) cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1(high) cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.

Wheler JJ, Parker BA, Lee JJ, et al.
Unique molecular signatures as a hallmark of patients with metastatic breast cancer: implications for current treatment paradigms.
Oncotarget. 2014; 5(9):2349-54 [PubMed] Free Access to Full Article Related Publications
Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.

Johnsen KB, Gudbergsson JM, Skov MN, et al.
A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy.
Biochim Biophys Acta. 2014; 1846(1):75-87 [PubMed] Related Publications
Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale.

Cao Z, Ding BS, Guo P, et al.
Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
Cancer Cell. 2014; 25(3):350-65 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

Ribeiro IP, Marques F, Caramelo F, et al.
Genetic imbalances detected by multiplex ligation-dependent probe amplification in a cohort of patients with oral squamous cell carcinoma-the first step towards clinical personalized medicine.
Tumour Biol. 2014; 35(5):4687-95 [PubMed] Related Publications
Oral tumors are a growing health problem worldwide; thus, it is mandatory to establish genetic markers in order to improve diagnosis and early detection of tumors, control relapses and, ultimately, delineate individualized therapies. This study was the first to evaluate and discuss the clinical applicability of a multiplex ligation-dependent probe amplification (MLPA) probe panel directed to head and neck cancer. Thirty primary oral squamous cell tumors were analyzed using the P428 MLPA probe panel. We detected genetic imbalances in 26 patients and observed a consistent pattern of distribution of genetic alterations in terms of losses and gains for some chromosomes, particularly for chromosomes 3, 8, and 11. Regarding the latter, some specific genes were highlighted due to frequent losses of genetic material--RARB, FHIT, CSMD1, GATA4, and MTUS1--and others due to gains--MCCC1, MYC, WISP1, PTK2, CCND1, FGF4, FADD, and CTTN. We also verified that the gains of MYC and WISP1 genes seem to suggest higher propensity of tumors localized in the floor of the mouth. This study proved the value of this MLPA probe panel for a first-tier analysis of oral tumors. The probemix was developed to include target regions that have been already shown to be of diagnostic/prognostic relevance for oral tumors. Furthermore, this study emphasized several of those specific genetic targets, suggesting its importance to oral tumor development, to predict patients' outcomes, and also to guide the development of novel molecular therapies.

Sugimoto K, Yoshida S, Mashio Y, et al.
Role of FGF10 on tumorigenesis by MS-K.
Genes Cells. 2014; 19(2):112-25 [PubMed] Related Publications
Murine MS-K and NFSA cell lines formed tumor after inoculation into mouse and both cell lines expressed high level of vascular endothelial growth factor-A (vegf-A) and produced same level of VEGF-A. However, poor blood vessel formation, and necrosis was significantly observed in NFSA-tumor, contrary to well-developed blood vessel formation in MS-K tumor. The microarray analysis showed high expression of fibroblast growth factor-10 (fgf-10) in MS-K than NFSA. In this report, the role of fgf-10 on tumor growth was studied. MS-K enhanced more proliferation of endothelial cells by direct co-culture than NFSA, and rFGF10 supported the proliferation of HUVEC in combination with VEGF-A. fgf-10-knocked down MS-K, MS-K (fgf-10-KD), proliferated slower in vitro and the tumorigenicity of them was also slower than control. The blood vessel formation in these MS-K (fgf-10-KD) clones was reduced compared with the MS-K (normal). qPCR analysis showed the suppression of vegf-A, vegf-C and fgfr-1-expression in the MS-K (fgf-10-KD) clones. Taken together, these results indicated that FGF10, which was produced from tumor cells, was essential for the proliferation of tumor cell itself and also supports proliferation of endothelial cells. Thus, FGF10 plays an important role for tumor growth by both paracrine and autocrine manner.

Shen YY, Lu YC, Shen DP, et al.
Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients.
World J Gastroenterol. 2013; 19(28):4568-75 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival.
METHODS: Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ(2) test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ(2) test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC.
RESULTS: In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ(2) = 3.589, P = 0.166) and alleles (χ(2) = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ(2) = 5.449, P = 0.020), well differentiated (log rank χ(2) = 12.798, P = 0.000), T1 or T2 stage (log rank χ(2) = 4.745, P = 0.029), without lymph node involvement (log rank χ(2) = 6.647, P= 0.010), and at an early clinical stage (log rank χ(2) = 4.615, P = 0.032).
CONCLUSION: Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.

Jardim DL, Conley A, Subbiah V
Comprehensive characterization of malignant phyllodes tumor by whole genomic and proteomic analysis: biological implications for targeted therapy opportunities.
Orphanet J Rare Dis. 2013; 8:112 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
BACKGROUND: Phyllodes tumors are uncommon breast tumors that account for less than 0.5% of all breast malignancies. After metastases develop, the prognosis is poor, with very few patients living more than 1 year. The biology of this unusual cancer is not understood and, consequently, no potential targets for treatments are currently available. There has been an exponential increase in the number of commercially available tumor profiling services. Herein, we report a case of metastatic malignant phyllodes tumor for which a comprehensive molecular analysis was performed by using Clinical Laboratory Improvement Amendments (CLIA)-certified labs, providing new insights into the potential opportunities for molecularly targeted therapies for this extremely rare disease.
METHODS: Next-generation sequencing was performed by using the FoundationOne™ platform (Foundation Medicine, Cambridge, MA). Whole-genome array-based comparative genomic hybridization (array CGH) was performed by using the DNAarray™ (CombiMatrix Diagnostics, Irvine, CA). Immunohistochemical and morphoproteomics analysis were performed at Consultative proteomics®, The University of Texas, UT Health Medical School, Houston,TX (Robert E Brown Lab); Clarient Diagnostics, Aliso Viejo, CA; and Caris Life Sciences Target one, Irving, TX, USA.
RESULTS: Next-generation sequencing showed 3 aberrant genes: activating mutation Q61L on NRAS; inactivating mutations Q504* and K740* on RB1; and TP53 loss. Whole-genome array-based comparative genomic hybridization (array CGH) revealed amplifications of chromosome (chr.) 1 (CKS1B gene), chr. 8 (MYC gene), and chr. 9 (CDKN2A gene) Deletions of chr. 17 (TP53), chr. 10 (GATA3), chr. 11 (FGF4 and CCND1 genes), and chr.22 (PDGFβ). Immunohistochemical analysis for relevant markers showed a positive staining for transducing-like enhancer of split (TLE) 3; secreted protein acidic and rich in cysteine (SPARC) was expressed at 2-3+ in the cytoplasm of the tumors cells, whereas mammalian target of rapamycin (mTOR) was expressed up to 2+ in the nuclei of the tumor cells.
CONCLUSIONS: We describe for the first time an NRAS mutation with concomitant activation of PI3K/Akt/mTOR in phyllodes tumor. We also found markers for sensitivity to taxane-based therapies, especially albumin-bound paclitaxel. Exploring the biology of rare malignancies by CLIA certified labs may be reasonable strategy for the development of targeted treatments.

Katoh M
Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review).
Int J Mol Med. 2013; 32(4):763-7 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Angiogenesis is a process of neovascular formation from pre-existing blood vessels, which consists of sequential steps for vascular destabilization, angiogenic sprouting, lumen formation and vascular stabilization. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin, Notch, transforming growth factor-β (TGF-β), Hedgehog and WNT signaling cascades orchestrate angiogenesis through the direct or indirect regulation of quiescence, migration and the proliferation of endothelial cells. Small-molecule compounds and human/humanized monoclonal antibodies interrupting VEGF signaling have been developed as anti-angiogenic therapeutics for cancer and neovascular age-related macular degeneration (AMD). Gene or protein therapy delivering VEGF, FGF2 or FGF4, as well as cell therapy using endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been developed as pro-angiogenic therapeutics for ischemic heart disease and peripheral vascular disease. Anti-angiogenic therapy for cancer and neovascular AMD is more successful than pro-angiogenic therapy for cardiovascular diseases, as VEGF-signal interruption is technically feasible compared with vascular re-construction. Common and rare genetic variants are detected using array-based technology and personal genome sequencing, respectively. Drug and dosage should be determined based on personal genotypes of VEGF and other genes involved in angiogenesis. As epigenetic alterations give rise to human diseases, polymer-based hydrogel film may be utilized for the delivery of drugs targeting epigenetic processes and angiogenesis as treatment modalities for cardiovascular diseases. Circulating microRNAs (miRNAs) in exosomes and microvesicles are applied as functional biomarkers for diagnostics and prognostics, while synthetic miRNAs in polymer-based nanoparticles are applicable for therapeutics. A more profound understanding of the spatio-temporal interactions of regulatory signaling cascades and advances in personal genotyping and miRNA profiling are required for the optimization of targeted therapy.

Zhang N, Li X, Wu CW, et al.
microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis.
Oncogene. 2013; 32(42):5078-88 [PubMed] Related Publications
Using microRNA (miRNA) expression array, we identified that miR-7 was deregulated in colorectal cancer (CRC). We studied the biological role and molecular target of miR-7 in CRC. miR-7 was downregulated in six out of seven colon cancer cell lines. Ectopic expression of miR-7 suppressed colon cancer cell proliferation (P<0.05), induced apoptosis (P<0.05) and caused cell-cycle arrest in G1 phase (P<0.05). The tumor suppressive function of miR-7 was further confirmed in nude mice (P<0.05). The 3'-untranslated region (3'UTR) of Yin Yang 1 (YY1) mRNA contains an evolutionarily conserved miR-7 binding site using in silico searches, luciferase reporter assay and western blot analysis confirmed that miR-7 directly bound to YY1 3'UTR to negatively regulate the protein expression of YY1 in colon cancer cell lines HCT116 and LOVO. Intriguingly, knock-down of YY1 in three colon cancer cell lines (HCT116, LOVO and DLD1) consistently suppressed cell proliferation (P<0.01) and induced apoptosis (P<0.01), indicating the opposite functions of miR-7 and YY1 in CRC. Consistent with these data, ectopic expression of YY1 promoted cell growth by increasing proliferation (P<0.01) and suppressing apoptosis (P<0.001). The tumorigenic ability of YY1 was further confirmed in vivo in xenograft-nude mouse model (P<0.01). In addition, pathway analyses revealed that the oncogenic effect by YY1 was associated with inhibiting p53 and modulating its downstream effectors p15, caspase cascades and C-Jun, and activating Wnt signaling pathway through activating β-catenin, anti-apoptotic survivin and fibroblast growth factor 4. Furthermore, multivariate analysis revealed that patients with YY1 protein high expression had a significant decrease in overall survival, and Kaplan-Meier survival curves showed that these patients had significantly shorter survival than others (P<0.0001). In conclusion, MiR-7 is a novel miRNA with tumor suppressive function in colon cancer by targeting oncogenic YY1. YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signaling pathways and serves as an independent prognostic biomarker for CRC patients.

Hillbertz NS, Hirsch JM, Jalouli J, et al.
Viral and molecular aspects of oral cancer.
Anticancer Res. 2012; 32(10):4201-12 [PubMed] Related Publications
Squamous cell carcinoma (SCC) is the most common epithelial malignancy in the oral cavity. SCCs and their variants constitute over 90% of oral malignancies, and the disease is associated with poor prognosis. OSCC is a complex malignancy where environmental factors, virus infections, and genetic alterations most likely interact, and thus give rise to the malignant condition. Herein, we review the available literature regarding high-risk factors such as alcohol and tobacco usage; discuss the roles of human papillomaviruses (HPV), the Epstein-Barr virus, and the human herpes simplex virus (HSV); and evaluate several candidate genes associated with the condition: p53, p16(INK4) and p21(WAF1/CIPI), survivin, B-cell lymphoma-2 (BCL-2), keratins, Fibroblast growth factor 3 (FGF3), FGF4, FGF19, Oral cancer overexpressed gene 1 (ORAOV1), and Cyclin D1 (CCND1).

Arao T, Ueshima K, Matsumoto K, et al.
FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma.
Hepatology. 2013; 57(4):1407-15 [PubMed] Related Publications
UNLABELLED: The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%-3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico-pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3.
CONCLUSION: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies.

Keshel SH, Soleimani M, Tavirani MR, et al.
Evaluation of unrestricted somatic stem cells as a feeder layer to support undifferentiated embryonic stem cells.
Mol Reprod Dev. 2012; 79(10):709-18 [PubMed] Related Publications
The use of unrestricted somatic stem cells (USSCs) holds great promise for future clinical applications. Conventionally, mouse embryonic fibroblasts (MEFs) or other animal-based feeder layers are used to support embryonic stem cell (ESC) growth; the use of such feeder cells increases the risk of retroviral and other pathogenic infection in clinical trials. Implementation of a human-based feeder layer, such as hUSSCs that are isolated from human sources, lowers such risks. Isolated cord blood USSCs derived from various donors were used as a novel, supportive feeder layer for growth of C4mES cells (Royan C4 ESCs). Complete cellular characterization using immunocytochemical and flow cytometric methods were performed on murine ESCs (mESCs) and hUSSCs. mESCs cultured on hUSSCs showed similar cellular morphology and presented the same cell markers of undifferentiated mESC as would have been observed in mESCs grown on MEFs. Our data revealed these cells had negative expression of Stat3, Sox2, and Fgf4 genes while showing positive expression for Pou5f1, Nanog, Rex1, Brachyury, Lif, Lifr, Tert, B2m, and Bmp4 genes. Moreover, mESCs cultured on hUSSCs exhibited proven differentiation potential to germ cell layers showing normal karyotype. The major advantage of hUSSCs is their ability to be continuously cultured for at least 50 passages. We have also found that hUSSCs have the potential to provide ESC support from the early moments of isolation. Further study of hUSSC as a novel human feeder layer may lead to their incorporation into clinical methods, making them a vital part of the application of human ESCs in clinical cell therapy.

Ziebart T, Draenert FG, Galetzka D, et al.
The original family revisited after 37 years: odontoma-dysphagia syndrome is most likely caused by a microduplication of chromosome 11q13.3, including the FGF3 and FGF4 genes.
Clin Oral Investig. 2013; 17(1):123-30 [PubMed] Related Publications
OBJECTIVES: Fibroblast growth factors consist of receptor tyrosine kinase binding proteins involved in growth, differentiation, and regeneration of a variety of tissues of the head and neck. Their role in the development of teeth has been documented, and their presence in human odontogenic cysts and tumors has previously been investigated. Odontoma–dysphagia syndrome (OMIM 164330) is a very rare disorder characterized by clustering of teeth as compound odontoma, dysplasia and aplasia of teeth, slight craniofacial abnormalities, and dysphagia. We have followed the clinical course of the disease in a family over more than 30 years and have identified a genetic abnormality segregating with the disorder.
MATERIALS AND METHODS: We evaluated clinical data from nine different family members and obtained venous blood probes for genetic studies from three family members (two affected and one unaffected).
RESULTS: The present family with five patients in two generations has remained one out of only two known cases with this very rare syndrome. All those affected showed teeth dysplasia, oligodontia, and dysplasia and odontoma of the upper and lower jaw. Additional signs included dysphagia and strictures of the oesophagus. Comorbidity in one patient included aortic stenosis and coronary artery disease, requiring coronary bypasses and aortic valve replacement. Genome-wide SNP array analyses in three family members (two affected and one unaffected) revealed a microduplication of chromosome 11q13.3 spanning 355 kilobases (kb) and including two genes in full length, fibroblast growth factors 3 (FGF3) and 4 (FGF4).
CONCLUSION: The microduplication identified in this family represents the most likely cause of the odontoma–dysphagia syndrome and implies that the syndrome is caused by a gain of function of the FGF3 and FGF4 genes.
CLINICAL RELEVANCE: Mutations of FGF receptor genes can cause craniofacial syndromes such as odontoma–dysphagia syndrome. Following this train of thought, an evaluation of FGF gene family in sporadic odontoma could be worthwhile.

Westerman BA, Braat AK, Taub N, et al.
A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation.
J Exp Med. 2011; 208(13):2675-89 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Despite intense investigation of intrinsic and extrinsic factors that regulate pluripotency, the process of initial fate commitment of embryonic stem (ES) cells is still poorly understood. We used a genome-wide short hairpin RNA screen in mouse ES cells to identify genes that are essential for initiation of differentiation. Knockdown of the scaffolding protein Mek binding protein 1 (Mp1, also known as Lamtor3 or Map2k1ip1) stimulated self-renewal of ES cells, blocked differentiation, and promoted proliferation. Fibroblast growth factor 4 (FGF4) signaling is required for initial fate commitment of ES cells. Knockdown of Mp1 inhibited FGF4-induced differentiation but did not alter FGF4-driven proliferation. This uncoupling of differentiation and proliferation was also observed when oncogenic Ras isoforms were overexpressed in ES cells. Knockdown of Mp1 redirected FGF4 signaling from differentiation toward pluripotency and up-regulated the pluripotency-related genes Esrrb, Rex1, Tcl1, and Sox2. We also found that human germ cell tumors (GCTs) express low amounts of Mp1 in the invasive embryonic carcinoma and seminoma histologies and higher amounts of Mp1 in the noninvasive carcinoma in situ precursor and differentiated components. Knockdown of Mp1 in invasive GCT cells resulted in resistance to differentiation, thereby showing a functional role for Mp1 both in normal differentiation of ES cells and in germ cell cancer.

Jordan NV, Johnson GL, Abell AN
Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer.
Cell Cycle. 2011; 10(17):2865-73 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Epithelial-mesenchymal transition (EMT) is an essential developmental program that becomes reactivated in adult tissues to promote the progression of cancer. EMT has been largely studied by examining the beginning epithelial state or the ending mesenchymal state without studying the intermediate stages. Recent studies using trophoblast stem (TS) cells paused in EMT have defined the molecular and epigenetic mechanisms responsible for modulating the intermediate "metastable" stages of EMT. Targeted inactivation of MAP3K4, knockdown of CBP, or overexpression of SNAI1 in TS cells induced similar metastable phenotypes. These TS cells exhibited epigenetic changes in the histone acetylation landscape that cause loss of epithelial maintenance while preserving self-renewal and multipotency. A similar phenotype was found in claudin-low breast cancer cells with properties of EMT and stemness. This intersection between EMT and stemness in TS cells and claudin-low metastatic breast cancer demonstrates the usefulness of developmental EMT systems to understand EMT in cancer.

Fan L, Wang Z, Liu J, et al.
A survey of green plant tRNA 3'-end processing enzyme tRNase Zs, homologs of the candidate prostate cancer susceptibility protein ELAC2.
BMC Evol Biol. 2011; 11:219 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
BACKGROUND: tRNase Z removes the 3'-trailer sequences from precursor tRNAs, which is an essential step preceding the addition of the CCA sequence. tRNase Z exists in the short (tRNase ZS) and long (tRNase ZL) forms. Based on the sequence characteristics, they can be divided into two major types: bacterial-type tRNase ZS and eukaryotic-type tRNase ZL, and one minor type, Thermotoga maritima (TM)-type tRNase ZS. The number of tRNase Zs is highly variable, with the largest number being identified experimentally in the flowering plant Arabidopsis thaliana. It is unknown whether multiple tRNase Zs found in A. thaliana is common to the plant kingdom. Also unknown is the extent of sequence and structural conservation among tRNase Zs from the plant kingdom.
RESULTS: We report the identification and analysis of candidate tRNase Zs in 27 fully sequenced genomes of green plants, the great majority of which are flowering plants. It appears that green plants contain multiple distinct tRNase Zs predicted to reside in different subcellular compartments. Furthermore, while the bacterial-type tRNase ZSs are present only in basal land plants and green algae, the TM-type tRNase ZSs are widespread in green plants. The protein sequences of the TM-type tRNase ZSs identified in green plants are similar to those of the bacterial-type tRNase ZSs but have distinct features, including the TM-type flexible arm, the variant catalytic HEAT and HST motifs, and a lack of the PxKxRN motif involved in CCA anti-determination (inhibition of tRNase Z activity by CCA), which prevents tRNase Z cleavage of mature tRNAs. Examination of flowering plant chloroplast tRNA genes reveals that many of these genes encode partial CCA sequences. Based on our results and previous studies, we predict that the plant TM-type tRNase ZSs may not recognize the CCA sequence as an anti-determinant.
CONCLUSIONS: Our findings substantially expand the current repertoire of the TM-type tRNase ZSs and hint at the possibility that these proteins may have been selected for their ability to process chloroplast pre-tRNAs with whole or partial CCA sequences. Our results also support the coevolution of tRNase Zs and tRNA 3'-trailer sequences in plants.

Leali D, Alessi P, Coltrini D, et al.
Long pentraxin-3 inhibits FGF8b-dependent angiogenesis and growth of steroid hormone-regulated tumors.
Mol Cancer Ther. 2011; 10(9):1600-10 [PubMed] Related Publications
Fibroblast growth factor-8b (FGF8b) exerts nonredundant autocrine/paracrine functions in steroid hormone-regulated tumors. Previous observations had shown that the soluble pattern recognition receptor long pentraxin-3 (PTX3) is a natural selective antagonist for a restricted number of FGF family members, inhibiting FGF2 but not FGF1 and FGF4 activity. Here, we assessed the capacity of PTX3 to antagonize FGF8b and to inhibit the vascularization and growth of steroid hormone-regulated tumors. Surface plasmon resonance analysis shows that PTX3 binds FGF8b with high affinity (K(d) = 30-90 nmol/L). As a consequence, PTX3 prevents the binding of FGF8b to its receptors, inhibits FGF8b-driven ERK1/2 activation, cell proliferation, and chemotaxis in endothelial cells, and suppresses FGF8b-induced neovascularization in vivo. Also, PTX3 inhibits dihydrotestosterone (DHT)- and FGF8b-driven proliferation of androgen-regulated Shionogi 115 (S115) mouse breast tumor cells. Furthermore, DHT-treated, PTX3 overexpressing hPTX3_S115 cell transfectants show a reduced proliferation rate in vitro and a limited angiogenic activity in the chick embryo chorioallantoic membrane and murine s.c. Matrigel plug assays. Accordingly, hPTX3_S115 cells show a dramatic decrease of their tumorigenic activity when grafted in immunodeficient male mice. These results identify PTX3 as a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity with possible implications for the therapy of hormonal tumors.

Karlsson E, Waltersson MA, Bostner J, et al.
High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1.
Genes Chromosomes Cancer. 2011; 50(10):775-87 [PubMed] Related Publications
The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.

Brown J, Bothma H, Veale R, Willem P
Genomic imbalances in esophageal carcinoma cell lines involve Wnt pathway genes.
World J Gastroenterol. 2011; 17(24):2909-23 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
AIM: To identify molecular markers shared across South African esophageal squamous cell carcinoma (ESCC) cell lines using cytogenetics, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) array copy number analysis.
METHODS: We used conventional cytogenetics, FISH, and multicolor FISH to characterize the chromosomal rearrangements of five ESCC cell lines established in South Africa. The whole genome copy number profile was established from 250K SNP arrays, and data was analyzed with the CNAT 4.0 and GISTIC software.
RESULTS: We detected common translocation breakpoints involving chromosomes 1p11-12 and 3p11.2, the latter correlated with the deletion, or interruption of the EPHA3 gene. The most significant amplifications involved the following chromosomal regions and genes: 11q13.3 (CCND1, FGF3, FGF4, FGF19, MYEOV), 8q24.21(C-MYC, FAM84B), 11q22.1-q22.3 (BIRC2, BIRC3), 5p15.2 (CTNND2), 3q11.2-q12.2 (MINA) and 18p11.32 (TYMS, YES1). The significant deletions included 1p31.2-p31.1 (CTH, GADD45α, DIRAS3), 2q22.1 (LRP1B), 3p12.1-p14.2 (FHIT), 4q22.1-q32.1 (CASP6, SMAD1), 8p23.2-q11.1 (BNIP3L) and 18q21.1-q21.2 (SMAD4, DCC). The 3p11.2 translocation breakpoint was shared across four cell lines, supporting a role for genes involved at this site, in particular, the EPHA3 gene which has previously been reported to be deleted in ESCC.
CONCLUSION: The finding that a significant number of genes that were amplified (FGF3, FGF4, FGF19, CCND1 and C-MYC) or deleted (SFRP2 gene) are involved in the Wnt and fibroblast growth factor signaling pathways, suggests that these pathways may be activated in these cell lines.

Sugahara K, Michikawa Y, Ishikawa K, et al.
Combination effects of distinct cores in 11q13 amplification region on cervical lymph node metastasis of oral squamous cell carcinoma.
Int J Oncol. 2011; 39(4):761-9 [PubMed] Related Publications
Lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC) is known to associate with a significant decrease of 5-year survival. Genetic factors related to the difference of the LNM status in the OSCC have been not fully elucidated. Array-based comparative genomic hybridization (CGH) with individual gene-level resolution and real-time quantitative polymerase chain reaction (QPCR) were conducted using primary tumor materials resected from 54 OSCC patients with (n=22) or without (n=32) cervical LNM. Frequent gain was observed at the 11q13 region exclusively in patients with cervical LNM, which was confirmed by real-time QPCR experiments using 11 genes (TPCN2, MYEOV, CCND1, ORAOV1, FGF4, TMEM16A, FADD, PPFIA1, CTTN, SHANK2 and DHCR7) in this region. It was revealed that two distinct amplification cores existed, which were separated by a breakpoint between MYEOV and CCND1 in the 11q13 region. The combination of copy number amplification at CTTN (core 2) and/or TPCN2/MYEOV (core 1), selected from each core, was most significantly associated with cervical LNM (P=0.0035). Two amplification cores at the 11q13 region may have biological impacts on OSCC cells to spread from the primary site to local lymph nodes. Further study of a larger patient series should be conducted to validate these results.

Nettersheim D, Gillis AJ, Looijenga LH, Schorle H
TGF-β1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma.
Int J Androl. 2011; 34(4 Pt 2):e189-203 [PubMed] Related Publications
Malignant germ-cell tumours arise from a neoplastic precursor, the carcinoma in situ, and develop into seminomas and/or non-seminomas (embryonal carcinomas, teratomas, yolk-sac tumours and choriocarcinomas). Based on histological and clinical findings, it has been postulated that seminomas can eventually transform into non-seminomas. Here, we used the cell line TCam-2 as model for seminomas and interrogated their differentiation potential. We demonstrate that TCam-2 cells are able to differentiate into mixed non-seminomatous lineages after supplementing the media with TGF-β1, EGF and FGF4. On a molecular level, the differentiation is initiated by repression of BMP/SMAD signalling. As a consequence, BLIMP1, a molecule known to inhibit the differentiation of murine primordial germ cells, is down-regulated and differentiation-inhibiting histone modifications are lost. The appearance of multinucleated giant cells and the expression of marker genes indicate that cells differentiate predominantly into extra-embryonic choriocarcinoma-like cells. This is most likely due to the presence of components of the Hippo pathway, TEAD4 and YAP1. These molecules have been described to trigger extra-embryonic fate determination in the murine system. This study supports the model that seminomas indeed have an intrinsic ability to transform into a non-seminoma. In addition, the data suggest that the transformation does not require an additional mutation, but can be triggered by changes in the tumour microenvironment.

Kumar M, Yigit M, Dai G, et al.
Image-guided breast tumor therapy using a small interfering RNA nanodrug.
Cancer Res. 2010; 70(19):7553-61 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Iron oxide nanoparticles offer a feasible tool for combined imaging and delivery of small interfering RNA (siRNA) to tumors, stimulating active interest in exploring different imaging and delivery platforms suitable for detection by a variety of modalities. In this study, we describe the synthesis and testing of a tumor-targeted nanodrug (MN-EPPT-siBIRC5) that is designed to specifically shuttle siRNA to human breast tumors. The nanodrug binds the tumor-specific antigen uMUC-1, which is found in >90% of human breast adenocarcinomas. MN-EPPT-siBIRC5 consists of superparamagnetic iron oxide nanoparticles [for magnetic resonance imaging (MRI)], the dye Cy 5.5 (for near-IR optical imaging), peptides (EPPT) that specifically target uMUC-1, and a synthetic siRNA that targets the tumor-specific antiapoptotic gene BIRC5. Nanodrug uptake by human breast adenocarcinoma cells resulted in a significant downregulation of BIRC5. Following i.v. delivery into subcutaneous mouse models of breast cancer, the nanodrug showed a preferential tumor uptake, which could be visualized by MRI and near-IR optical imaging. Furthermore, MRI could be used to quantitatively monitor nanodrug bioavailability in the tumor tissue throughout the course of treatment. Intravenous injection of the agent once a week over 2 weeks resulted in the induction of considerable levels of necrosis and apoptosis in the tumors, translating into a significant decrease in tumor growth rate. Our strategy permits the simultaneous tumor-specific delivery of siRNA to tumors and the imaging of the delivery process. More generally, it illustrates the potential to apply this approach to many human cancer studies, including for basic tumor biology and therapy.

Kim S, Lim B, Kim J
EWS-Oct-4B, an alternative EWS-Oct-4 fusion gene, is a potent oncogene linked to human epithelial tumours.
Br J Cancer. 2010; 102(2):436-46 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
BACKGROUND: Characterisation of EWS-Oct-4 translocation fusion product in bone and soft-tissue tumours revealed a chimeric gene resulting from an in-frame fusion between EWS (Ewing's sarcoma gene) exons 1-6 and Oct-4 exons 1-4. Recently, an alternative form of the fusion protein between the EWS and Oct-4 genes, named EWS-Oct-4B, was reported in two types of epithelial tumours, a hidradenoma of the skin and a mucoepidermoid carcinoma of the salivary glands. As the N-terminal and POU domains of the EWS-Oct-4 and EWS-Oct-4B proteins are not structurally identical, we decided to investigate the functional consequences of the EWS-Oct-4B fusion.
METHODS: In this report, we have characterised the EWS-Oct-4B fusion protein. To investigate how the EWS-Oct-4B protein contributes to tumourigenesis in human cancers, we analysed its DNA-binding activity, subcellular localisation, transcriptional activation behaviour, and oncogenic properties.
RESULTS: We found that this new chimeric gene encodes a nuclear protein that binds DNA with the same sequence specificity as the parental Oct-4 protein or the fusion EWS-Oct-4 protein. We show that the nuclear localisation signal of EWS-Oct-4B is dependent on the POU DNA-binding domain, and we identified a cluster of basic amino acids, (269)RKRKR(273), in the POU domain that specifically mediates the nuclear localisation of EWS-Oct-4B. Comparison of the properties of EWS-Oct-4B and EWS-Oct-4 indicated that EWS-Oct-4B is a less-potent transcriptional activator of a reporter construct carrying the Oct-4-binding sites. Deletion analysis of the functional domains of EWS-Oct-4B revealed that the EWS N-terminal domain (NTD)(B), POU, and C-terminal domain (CTD) are necessary for its full transactivation potential. Despite its reduced activity as a transcriptional activator, EWS-Oct-4B regulated the expression of fgf-4 (fibroblast growth factor-4) and nanog, which are potent mitogens, as well as of Oct-4 downstream target genes, the promoters of which contain potential Oct-4-binding sites. Finally, ectopic expression of EWS-Oct-4B in Oct-4-null ZHBTc4 ES cells resulted in increased tumourigenic growth potential in nude mice.
CONCLUSION: These results suggest that the oncogenic effect of the t(6;22) translocation is due to the EWS-Oct-4B chimeric protein, and that alternative fusion of the EWS amino terminal domain to the Oct-4 DNA-binding domain produces another transforming chimeric product in human epithelial tumours.

Trepel M, Stoneham CA, Eleftherohorinou H, et al.
A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer.
Mol Cancer Ther. 2009; 8(8):2383-91 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Suicide gene transfer is the most commonly used cytotoxic approach in cancer gene therapy; however, a successful suicide gene therapy depends on the generation of efficient targeted systemic gene delivery vectors. We recently reported that selective systemic delivery of suicide genes such as herpes simplex virus thymidine kinase (HSVtk) to tumor endothelial cells through a novel targeted adeno-associated virus/phage vector leads to suppression of tumor growth. This marked effect has been postulated to result primarily from the death of cancer cells by hypoxia following the targeted disruption of tumor blood vessels. Here, we investigated whether an additional mechanism of action is involved. We show that there is a heterotypic "bystander" effect between endothelial cells expressing the HSVtk suicide gene and tumor cells. Treatment of cocultures of HSVtk-transduced endothelial cells and non-HSVtk-transduced tumor cells with ganciclovir results in the death of both endothelial and tumor cells. Blocking of this effect by 18alpha-glycyrrhetinic acid indicates that gap junctions between endothelial and tumor cells are largely responsible for this phenomenon. Moreover, the observed bystander killing is mediated by connexins 43 and 26, which are expressed in endothelial and tumor cell types. Finally, this heterotypic bystander effect is accompanied by a suppression of tumor growth in vivo that is independent of primary gene transfer into host-derived tumor vascular endothelium. These findings add an alternative nonmutually exclusive and potentially synergistic cytotoxic mechanism to cancer gene therapy based on targeted adeno-associated virus/phage and further support the promising role of nonmalignant tumor stromal cells as therapeutic targets.

Lázár V, Ecsedi S, Szöllosi AG, et al.
Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma.
Mod Pathol. 2009; 22(10):1367-78 [PubMed] Related Publications
Amplification of the 11q13 chromosomal region is a common event in primary melanomas. Several candidate genes are localized at this sequence; however, their role in melanoma has not been clearly defined. The aim of this study was to develop an accurate method for determining the amplification pattern of six candidate genes that map to this amplicon core and to elucidate the possible relationship between BRAF, NRAS mutations and CCND1 copy number alterations, all of which are key components of the MAP kinase pathway. Characterization of gene copy numbers was performed by quantitative PCR and, as an alternative method, fluorescence in situ hybridization was used to define the CCND1 amplification pattern at the single cell level. Samples with amplified CCND1 (32%) were further analyzed for copy number alterations for the TAOS1, FGF3, FGF19, FGF4 and EMS1 genes. Co-amplification of the CCND1 and TAOS1 was present in 15% of tumors and was more frequent in ulcerated lesions (P=0.017). Furthermore, 56% of primary melanomas had either BRAF or NRAS mutations, but these two mutations were not present in any of the lesions analyzed. Of these cases, 34% also had CCND1 amplification. There was a significant relationship between NRAS activating mutations and UV exposure (P=0.005). We did not find correlations between CCND1 gene amplification status and any of the patients' clinicopathological parameters. However, CCND1 amplification simultaneously with either BRAF or NRAS activation mutations was observed mainly in primary tumors with ulcerated surfaces (P=0.028). We assume that co-amplification of these candidate genes in the 11q13 region or CCND1 gene alterations along with either BRAF or NRAS mutations might be more important for prognosis than the presence of these alterations alone.

Hartmann O, Spyratos F, Harbeck N, et al.
DNA methylation markers predict outcome in node-positive, estrogen receptor-positive breast cancer with adjuvant anthracycline-based chemotherapy.
Clin Cancer Res. 2009; 15(1):315-23 [PubMed] Related Publications
PURPOSE: We have shown that DNA methylation of the PITX2 gene predicts risk of distant recurrence in steroid hormone receptor-positive, node-negative breast cancer. Here, we present results from a multicenter study investigating whether PITX2 and other candidate DNA methylation markers predict outcome in node-positive, estrogen receptor-positive, HER-2-negative breast cancer patients who received adjuvant anthracycline-based chemotherapy.
EXPERIMENTAL DESIGN: Using a microarray platform, we analyzed DNA methylation in regulatory regions of PITX2 and 60 additional candidate genes in 241 breast cancer specimens. Using Cox regression analysis, we assessed the predictive power of the individual marker/marker panel candidates. Clinical endpoints were time to distant metastasis, disease-free survival, and overall survival. A nested bootstrap/cross-validation strategy was applied to identify and validate marker panels.
RESULTS: DNA methylation of PITX2 and 14 other genes was correlated with clinical outcome. In multivariate models, each methylation marker added significant information to established clinical factors. A four-marker panel including PITX2, BMP4, FGF4, and C20orf55 was identified that resulted in improvement of outcome prediction compared with PITX2 alone.
CONCLUSIONS: This study provides further evidence for the PITX2 biomarker, which has now been successfully confirmed to predict outcome among different breast cancer patient populations. We further identify new DNA methylation biomarkers, three of which can be combined into a panel with PITX2 to increase the outcome prediction performance in our anthracycline-treated primary breast cancer population. Our results show that a well-defined panel of DNA methylation markers enables outcome prediction in lymph node-positive, HER-2-negative breast cancer patients treated with anthracycline-based chemotherapy.

Chang CC, Shieh GS, Wu P, et al.
Oct-3/4 expression reflects tumor progression and regulates motility of bladder cancer cells.
Cancer Res. 2008; 68(15):6281-91 [PubMed] Related Publications
Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. Here, we show that in clinical samples bladder tumors with intense expression of stem cell marker Oct-3/4 (also known as POU5F1) are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. Expression of Oct-3/4 is detected in human bladder transitional cell carcinoma samples and cell lines. Overexpression of Oct-3/4 enhances, whereas knockdown of Oct-3/4 expression by RNA interference reduces, migration and invasion of bladder cancer cells. Oct-3/4 can up-regulate fibroblast growth factor-4 and matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-13 production, which may contribute to tumor metastasis. Finally, we show that Ad5WS4, an E1B-55 kD-deleted adenovirus driven by the Oct-3/4 promoter, exerts potent antitumor activity against bladder cancer in a syngeneic murine tumor model. Therefore, our results implicate that Oct-3/4 may be useful as a novel tumor biological and prognostic marker and probably as a potential therapeutic target for bladder cancer.

Katoh M
Cancer genomics and genetics of FGFR2 (Review).
Int J Oncol. 2008; 33(2):233-7 [PubMed] Related Publications
FGFR2 gene encodes FGFR2b in epithelial cells, and FGFR2c in mesenchymal cells. FGFR2b is a high affinity receptor for FGF1, FGF3, FGF7, FGF10 and FGF22, while FGFR2c for FGF1, FGF2, FGF4, FGF6, FGF9, FGF16 and FGF20. Here genomics and genetics of FGFR2, and therapeutics targeted to FGFR2 will be reviewed. Single nucleotide polymorphisms (SNPs) of FGFR2 are associated with increased risk of breast cancer. Gene amplification or missense mutation of FGFR2 occurs in gastric cancer, lung cancer, breast cancer, ovarian cancer, and endometrial cancer. Genetic alterations of FGFR2 induce aberrant FGFR2 signaling activation due to release of FGFR2 from autoinhibition, or creation of FGF signaling autocrine loop. Class switch of FGFR2b to FGFR2c is associated with more malignant phenotype. FGF and canonical WNT signals synergize during mammary carcinogenesis, but counteract during osteogenesis and adipogenesis. Among PD173074, SU5402, and AZD2171 functioning as FGFR inhibitors, AZD2171 is the most promising anti-cancer drug. Cancer genomics and genetics are utilized to predict cancer-driving pathway for therapeutic optimization. FGFR2ome is defined as a complete data set of SNP, copy number variation (CNV), missense mutation, gene amplification, and predominant isoform of FGFR2. FGFR2ome analyses in patients with several tumor types among various populations should be carried out to establish integrative database of FGFR2 for the rational clinical application of FGFR2-targeted cancer therapy.

Koletsa T, Kostopoulos I, Charalambous E, et al.
A splice variant of HER2 corresponding to Herstatin is expressed in the noncancerous breast and in breast carcinomas.
Neoplasia. 2008; 10(7):687-96 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Herstatin (HST) is an alternatively spliced HER2 product with growth-inhibitory properties in experimental cancer systems. The role of HST in adult human tissues and disease remains unexplored. Here, we investigated HST expression at the mRNA and protein (immunohistochemistry [IHC]) level in parallel with parameters reflecting HER activation in 187 breast carcinomas and matched noncancerous breast tissues (NCBT). Noncancerous breast tissues demonstrated the highest HST/HER2 transcript ratios corresponding to a few positive epithelial and stromal cells by IHC. Although HST/HER2 transcript ratios in tumors were inversely associated with HER2 IHC grading (P = .0048 for HER2 IHC-1+ and P = .0006 for HER2 IHC-2+ vs HER2-negative tumors), relative HST expression within the same tumor/NCBT system remained constant. HST/HER2 ratios did not predict the presence of HST protein, which was found in 46 (25%) of 187 tumors. A subgroup of HER2 IHC-3+ tumors exhibited high HST/HER2 transcript ratios, strong HST protein positivity, and cytoplasmic phospho-Akt/PKB and p21(CIP1/WAF1) localization. In conclusion, HST may act as a paracrine factor in the adult breast. Because HST is described as an endogenous pan-HER inhibitor, the presence of this protein in breast carcinomas may portent the inefficiency of exogenous efforts to block HER2 dimerization, whereas its absence may justify such interventions.

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