Oncogene (2007) 26, 142–147 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc SHORT COMMUNICATION TRAF4 overexpression is a common characteristic of human carcinomas

S Camilleri-Broe¨ t1,2, I Cremer1, B Marmey2, E Comperat3, F Viguie´ 2, J Audouin2, M-C Rio4, W-H Fridman1, C Saute` s-Fridman1 and CH Re´ gnier1

1Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Unite´ 255 d’Immunologie Cellulaire et Clinique, Universite´ Pierre et Marie Curie Paris VI, Universite´ Paris-Descartes, Faculte´ de Me´decine, Centre de Recherches Biome´dicales des Cordeliers, Paris, France; 2Universite´ Paris-Descartes, Faculte´ de Me´decine, AP-HP Hoˆtel-Dieu, Paris, France; 3Universite´ Pierre et Marie Curie Paris VI, Faculte´ de Me´decine, AP-HP La Pitie´-Salpeˆtrie`re, Paris, France and 4Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), De´partement de Pathologie Mole´culaire, UPR 6520 CNRS, INSERM U596, Universite´ Louis Pasteur, Illkirch, France

Tumor necrosis factor receptor (TNFR) associatedfactor including a carboxy-terminal TRAF domain, are 4 (TRAF4) was initially identifiedasa gene amplifiedand encoded by the mammalian genome. Their main overexpressedin breast carcinomas. Our aim was to functions are exerted in the immune system where they evaluate whether TRAF4 protein overexpression exists in regulate intracellular signalling pathways leading to the other cancer types. Immunohistochemistry analysis of activation of a common set of transcription factors tumor samples from 623 patients with 20 different tumor including NF-kB and AP-1 (Aggarwal, 2003). types showedthat TRAF4 was overexpressedin 268 Unlike other members of the TRAF family, the tumors (43%), including 82 of 137 lung adenocarcinomas biological function of TRAF4 remains elusive. Several (60%). Interestingly, 32 primary tumors andtheir reports suggested that TRAF4 could be recruited to matching metastases exhibitedmostly similar TRAF4 different TNFRand TLRsignalling pathways (Kra- expression pattern. TRAF4 protein overexpression was jewska et al., 1998; Ye et al., 1999; Esparza and Arch, limitedto cancer cells andthe subcellular localization was 2004; Takeshita et al., 2005), and in mitogen-activated consistently cytoplasmic in a large majority of cases. To protein kinase (MAPK) pathways (Xu et al., 2002; Abell investigate changes in TRAF4 gene copy number, 125 and Johnson, 2005; Li et al., 2005) but in vivo evidence cases from six different types of carcinomas were also of such a role is still missing. Mice deficient for TRAF4 analysedby fluorescence in situ hybridization. Out of the exhibit clear ontogenic defects affecting neural tube 28 cases (22%) showing an increased TRAF4 gene copy closure, tracheal formation and skeletal patterning, number, 23 (82%) were overexpressing the protein. Thus, phenotypes that might be linked to abnormal cell TRAF4 gene amplification is one of the mechanisms migration (Regnier et al., 2002). responsible for TRAF4 protein overexpression in human TRAF4 was the first member of the TRAF protein cancers. Considering that TRAF4 is locatedat 17q11.2 in family found upregulated in human carcinomas. Indeed, a region of amplification devoid of known oncogenes and the TRAF4 cDNA was initially isolated from metastatic is commonly overexpressedin cancer, our datasupport an breast cancer (Regnier et al., 1995; Tomasetto et al., oncogenic role for TRAF4. 1995), where the TRAF4 gene was amplified, leading to Oncogene (2007) 26, 142–147. doi:10.1038/sj.onc.1209762; overexpression of the gene product (Bieche et al., 1996). published online 26 June 2006 Detailed analysis of the amplification pattern of five genes located on the long arm of the chromosome 17, Keywords: TRAF4; chromosome 17q11; ERBB2; including the ERBB2 oncogene (Slamon et al., 1989), amplification; lung revealed the existence of at least two different regions of amplification in breast tumors (Bieche et al., 1996). The first amplicon includes ERBB2 and is well-characterized (Kauraniemi et al., 2001) whereas the second amplicon, closer to the centromere, contains TRAF4. The existence TRAF proteins belong to a family of cytoplasmic of a distinct region of amplification at 17q11.2 contain- adaptors involved in the signalling cascade activated ing TRAF4 was confirmed by detailed analysis of genetic by receptors of the TNFRand interleukin-1/Toll-like changes along the long arm of chromosome 17 in breast receptor (IL-1R/TLR) families (Chung et al., 2002). Six carcinoma cell lines and biopsies (Kauraniemi et al., TRAF proteins that share common structural features, 2001; Pollack et al., 2002). While previous studies have measured TRAF4 gene Correspondence: Dr CH Re´ gnier, INSERM U255, Centre de expression at the level of transcription in breast Recherches Biome´ dicales des Cordeliers, 15 rue de l’Ecole de carcinomas, we report here, the analysis of TRAF4 Me´ decine, Paris 75006, France. E-mail: [email protected] protein expression in a large series of human cancers. Received 13 February 2006; revised 13 April 2006; accepted 18 May Among the 623 tissue sections from 20 different tumor 2006; published online 26 June 2006 types that were screened for the expression of TRAF4 Amplification and overexpression of TRAF4 in cancer S Camilleri-Broe¨t et al 143 using immunohistochemistry, 268 (43%) cases from 18 (55/88; 63%) and node positive (27/49; 55%) cases different origins showed overexpression and were stained positive for TRAF4. considered TRAF4 positive. TRAF4 staining was TRAF4 expression pattern was also examined in detected in the cancer cells and not in the underlying primary tumors and metastases. First, among the 121 stroma (Figure 1). TRAF4 protein overexpression was colon adenocarcinomas analysed in our series, 108 were most commonly observed in epithelial tumors (48%), primary tumors and 13 were unmatched lung-metastases but also in 31% of melanomas, 21% of neurogenic of colon adenocarcinomas. The detailed analysis of tumors and 17% of lymphomas. However, it was not TRAF4 overexpression in these two groups suggested detected in insulinoma (seven cases) or in follicular that it was more frequently detected in visceral lymphoma (seven cases). In epithelial tumors, TRAF4 metastases (7/13; 54%) than in primary colon adeno- was overexpressed in approximately 60% of lung, carcinomas (27/108; 25%). However, this difference was breast and ovarian, 44% of bladder and 28% of limit of significance (Fisher’s exact probability test, colon carcinomas (Table 1). Among these cases, TRAF4 P ¼ 0.046). Second, both the primary tumor and the was strongly overexpressed (2 þ ) in 32% of breast associated metastasis from the same patient were (Figure 1b), 24% of lung (Figure 1h), 12% of ovary obtained in 32 cases (13 ovary peritoneal metastases, (Figure 1d) and 11% of colon adenocarcinomas 11 lung, 4 colon and 4 breast lymph node metastases). In (Figure 1f). Thus, TRAF4 protein overexpression most of the cases (28/32; 88%), similar expression is a common feature of several human cancers. pattern of TRAF4 was observed in the primary tumor In a meta-analysis of human cancer cDNA microarray and the matching metastasis. The four discordant cases studies, TRAF4 belongs to a common transcriptional corresponded to either a loss or a gain of TRAF4 profile of 67 genes that are universally activated in expression and were likely linked to tumor heterogeneity most cancer types (Rhodes et al., 2004). In the analysed by tissue microarrays. This suggests that latter report, TRAF4 mRNA is overexpressed in TRAF4 upregulation is more likely gained at an early lung adenocarcinoma, small cell lung carcinoma, ovary, stage of tumorigenesis rather than being acquired during colon and prostate carcinomas, which is in agreement cancer progression. Accordingly, gene expression pro- with our data. Unlike transcriptome analyses of files of primary breast carcinomas have revealed that cancer samples, which do not provide information genetic changes in the primary tumors are generally regarding cellular origin and subcellular localization of retained in their matching metastasis (Perou et al., 2000; individual gene products, our study demonstrates clearly Weigelt et al., 2003). that overexpression of TRAF4 protein is limited to To decipher the mechanism for deregulated expres- cancer cells. sion of TRAF4, we performed FISH analysis on TMA The subcellular localization of TRAF4 was restricted slides containing 125 TRAF4-positive and negative to the cytoplasm in 79% of the tumors examined and tumor samples from breast, ovary, lung, colon, pancreas representative examples of cytoplasmic staining are and thyroid origins. As shown on Figure 1j and k, a shown in Figure 1b, d, f and h. This was expected from maximum of 10 TRAF4 gene copies per tumor cell was earlier studies on TRAF4 localization in normal adult seen. Homogenous spread of the TRAF4 probe was tissues (Krajewska et al., 1998), endothelial cells (Li observed in interphase nuclei without cluster pattern. et al., 2005) and cells transiently overexpressing TRAF4 We found that the TRAF4 gene copy number is (Krajewska et al., 1998; Glauner et al., 2002; Sax and El- increased in some cases of all cancer types tested, except Deiry, 2003). However, 10% of all cases exhibited both in thyroid carcinomas (Table 2). Overall in 22% nuclear and cytoplasmic labelling whereas 11% showed (28/125) of cases, a gain in TRAF4 gene copy was exclusively nuclear staining (Table 1). TRAF4 nuclear found and it was associated to protein overexpression in localization was reported previously in invasive breast 82% (23/28). In particular, FISH analysis revealed that carcinoma (Regnier et al., 1995) and further investigated overrepresentation or amplification of the TRAF4 gene in vitro by transient expression of GFP-tagged deletion was associated with protein overexpression in pancreas mutants that predominantly localized to the nucleus in (3/3; 100%), breast (2/2; 100%), lung (15/18; 83%), HeLa cells (Glauner et al., 2002). As TRAF4 nuclear ovary (2/3; 67%) and colon (1/2; 50%) carcinoma localization was not seen in normal tissues (Krajewska samples (Table 2). Among these 23 tumor samples with et al., 1998), changes in TRAF4 protein subcellular combined TRAF4 gene amplification and overexpres- localization could be specific of the tumoral context. sion, 17 (74%) showed a strong TRAF4 immunostain- From our current knowledge, the mechanism and ing (2 þ ), which suggests that increased TRAF4 gene biological consequence of this nuclear localization of copy number is associated to higher level of TRAF4 TRAF4 remain unknown. protein expression. Aside from high levels of amplifica- Association between TRAF4 overexpression and tion of known oncogenes, genome-wide analysis of gene nodal status was investigated in colon and lung copy number alterations in cancer revealed that the adenocarcinomas. Among the 108 primary colon majority of transcriptional variations are due to low adenocarcinomas, there was no significant difference in level copy number changes (Hyman et al., 2002; Wolf TRAF4 overexpression between node negative (16/62; et al., 2004). In our study, the TRAF4 gain observed in 26%) and node positive (11/46; 24%) patients. Simi- 22% of all cases was moderate (up to 10 copies) but it larly, among 137 lung adenocarcinomas, no significant was significantly associated with gene expression. The difference was found in the number of node negative common criterion for designating a gene as a putative

Oncogene Amplification and overexpression of TRAF4 in cancer S Camilleri-Broe¨t et al 144 target of an amplicon is that amplification leads to its adenocarcinomas, using a chromosome 17 centromeric overexpression (Collins et al., 1998). We show that probe as control. Overall, TRAF4 gain was found in amplification represents one of the mechanisms leading 11/31 (35%) and ERBB2 in 6/31 (19%) tumor samples. to overexpression of the TRAF4 protein in most cancer Six out of the 11 cases with TRAF4 gain had no gain of types tested. Our findings are therefore in good ERBB2 and/or CEN17 (Figure 2). In the five remaining agreement with the hypothesis that TRAF4 is a target cases, a larger chromosomal region was involved, of a distinct amplification region at 17q11. including both TRAF4 and ERBB2 genes. Among them, Amplification of the TRAF4 and ERBB2 genes was two cases showed a genetic gain of TRAF4, ERBB2 analysed in parallel in 31 samples of primary lung and CEN17, reflecting increased copy number of

Oncogene Amplification and overexpression of TRAF4 in cancer S Camilleri-Broe¨t et al 145 chromosome 17 (Figure 2). This indicates that TRAF4 lung adenocarcinomas concerned and it is due to gene gene amplification can occur independently of ERBB2 amplification in about 38% of the cases. Interestingly, gain in lung carcinomas. Amplification at 17q has been TRAF4 is found amplified independently of ERBB2 in extensively investigated in breast cancer (Orsetti et al., more than half of these cases. Our data emphasize that 2004). However, genetic gains of chromosome 17q TRAF4 represents a novel common target of deregula- have also been reported in lung adenocarcinomas but tion in lung cancer. the nature of the genes concerned by this genetic The May 2004 (hg17) human genome assembly was alteration remains poorly investigated (Balsara and analysed with the UCSC Genome Browser (http:// Testa, 2002). ERBB2 is expressed in about 30% of genome.ucsc.edu/) to identify the genes contained in Non-Small Cell Lung Carcinomas (NSCLC), especially the 178 kb insert of the BAC clone RP11-386F9 used for adenocarcinomas, although gene amplification is not FISH analysis. This BAC clone harbors seven tran- usually the underlying mechanism (Hirsch et al., 2002). scribed genes localized in the 17q11.2 sub-band. Among In our analysis, TRAF4 overexpression was most these genes, only SDF2, NEK8 and TRAF4 have been commonly detected in this cancer type with 60% of found upregulated at the mRNA level in breast cancer

Table 1 Expression and localization of TRAF4 in different types of human tumors Tumors Cases Cytoplasmic Cytoplasmic and nuclear Nuclear Total positive %

Epithelial tumors 496 191 25 24 240 48 Lung adenocarcinoma 137 57 13 12 82 60 Squamous cell lung carcinoma 55 27 8 0 35 64 Small cell lung carcinoma 5 2 0 0 2 40 Colon adenoarcinoma 121 29 0 5 34 28 Pancreatic adenocarcinoma 7 5 0 0 5 71 Ovary adenocarcinoma 25 11 1 2 14 56 Breast adenocarcinoma 25 11 1 3 15 60 Prostatic adenocarcinoma 12 6 0 1 7 58 Bladder carcinoma 80 33 1 1 35 44 Kidney carcinoma 9 4 0 0 4 44 Carcinoid tumor 7 2 1 0 3 43 Insulinoma 7 0 0 0 0 0 Thyroid papillary carcinoma 6 4 0 0 4 67

Lymphomas 53 6 0 3 9 17 Diffuse large B cell lymphoma 35 6 0 0 6 17 Hodgkin’s disease 11 0 0 3 3 27 Follicular lymphoma 7 0 0 0 0 0

Other tumors 74 15 1 3 19 26 Neurogenic tumors 19 4 0 0 4 21 Malignant pleural mesothelioma 30 3 0 1 4 13 Seminoma 9 4 1 1 6 58 Melanoma 16 4 0 1 5 31

Total 623 212 26 30 268 43

TRAF4 immunostaining was considered negative when less than 5% of tumoral cells were stained, 1+ when TRAF4 was faintly or heterogeneously expressed in the cytoplasm in less than 50% of tumor cells and/or in the nucleus, and 2+ when TRAF4 was brightly expressed in the cytoplasm in more than 50% of tumor cells. Nuclear staining and cytoplasmic score 1+ and 2+ were considered overexpressed. Numbers of cases studied are indicated. %: percentage of TRAF4 positive cases per tumor type.

Figure 1 TRAF4 is overexpressed and amplified in human cancers. TRAF4 immunohistochemical staining in breast (a, b), ovary (c, d), colon (e, f) and lung (g, h) adenocarcinomas was homogeneous throughout each tumor sample and detects cytoplasmic overexpression in the four different types of cancer (b, d, f and h)( 40 magnification). The anti-TRAF4 monoclonal antibody 5MLN- 2H1 was previously described (Regnier et al., 2002). The conditions for detecting TRAF4 above the basal level of expression were assessed using serial antibody dilutions on paraffin sections of HEK 293 cells stably overexpressing TRAF4 versus sections of wild-type cells. Using a 1:200 dilution, the TRAF4-transfected HEK 293 cells showed a cytoplasmic labeling in 80% of cells whereas no staining was seen in control cells (data not shown). Immunohistochemical analysis was performed retrospectively either on conventional slides or on TMA sections for 623 formalin-fixed, paraffin-embedded tissues, including 496 cases of epithelial tumors (452 primary tumors, 31 lymph node metastases of lung cancer and 13 colon derived lung metastases) from the department of Pathology, Hoˆ tel-Dieu Hospital, Paris. After antigen retrieval (Target Retrieval Solution pH 9.9, DakoCytomation), 3 mm sections were incubated with the anti-TRAF4 antibody (1:200). The immunoreactivity was revealed with a commercially available streptavidin-biotin-peroxidase kit (Abcys). FISH analysis done on interphase nuclei of breast (i, j) and lung (k) adenocarcinomas shows 17q11.2 amplification (j, k). The methylrhodamine-labeled probe was generated from the chromosomal region that contains TRAF4 (BAC clone RP11-386F9) using the nick translation kit (Roche Diagnostics) and FISH was performed on TMA slides. Signal was visualized under a fluorescent microscope (Olympus BX41) at  1000 magnification.

Oncogene Amplification and overexpression of TRAF4 in cancer S Camilleri-Broe¨t et al 146 Table 2 Association between TRAF4 gene amplification detected by p13 FISH and TRAF4 protein overexpression analysed by IHC in 125 p12 adenocarcinomas of different origins p11.2 p11.1 CEN17 TumorsCasesFISH-IHC À FISH-IHC+ FISH+IHCÀ FISH+IHC+ q11.1 q11.2 q12 q21 Breast 9 3 4 0 2 TRAF4 Ovary 23 7 13 1 2 q22 Lung 63 22 23 3 15 q23 17q11.2 Colon 20 13 5 1 1 q24 Pancreas 5 1 1 0 3 q25 ERBB2 Thyroid 5 1 4 0 0 17q12 Total 125 47 50 5 23 19 2 3 2 4 1 Fluorescence in situ hybridization revealed TRAF4 amplification Figure 2 Analysis of TRAF4 and ERBB2 gene amplifications in (FISH+) or no change in copy number (FISHÀ). Immunohistochem- 31 cases of primary lung adenocarcinomas by FISH. Columns istry was scored positive (IHC+) or negative (IHCÀ) for TRAF4 indicate the amplification pattern of the CEN17, TRAF4 and overexpression. Numbers of cases studied are indicated. The correla- ERBB2 FISH probes in the centromeric, 17q11.2 and 17q12 tion between TRAF4 amplification and overexpression is statistically regions, respectively. ERBB2 and CEN17 were detected with the significant (Pearson’s chi-square, P ¼ 0.005, n ¼ 125). dual-colour HER2 FISH pharmDx Kit (DakoCytomation). Gene copy number was scored as follows: o4 gene copies per nucleus, no amplification (white); four to six gene copies per nucleus, overrepresentation (grey); and >6 gene copies per nucleus, tissues. Both SDF2 and TRAF4 showed a link between amplification (black). Numbers correspond to the number of cases gene amplification and mRNA overexpression in breast exhibiting the corresponding profile. The bracket on the idiogram tumors (Pollack et al., 2002). NEK8 is the direct indicates the probes position on chromosome 17. neighbor of the TRAF4 gene at 17q11.2 and was reported overexpressed at the mRNA level in breast tumors (Bowers and Boylan, 2004). Considering the protein is likely to play an important role in carcinogen- nature of gene amplification, SDF2 and NEK8 are likely esis. A very recent report shows that TRAF4 partici- to be co-amplified with TRAF4 in other cancer types. pates in endothelial cell migration within focal However, they were not reported in the meta-analysis as complexes (Wu et al., 2005). Considering the importance commonly upregulated in human cancers (Rhodes et al., of cell migration in cancer, we could hypothesize that 2004). This suggests that TRAF4 represents the best TRAF4 upregulation could participate in and/or candidate driver gene of the amplification at 17q11. promote tumorigenesis. To date, TRAF4 is the first TRAF protein known to be amplified and/or overexpressed in a wide-range of human malignancies. Overexpression of TRAF4 protein Acknowledgements is the consequence of its gene amplification in about a quarter of human carcinomas. As occurs for established We thank DJ Heard for critical reading of the manuscript, C oncogenes such as ERBB2 and MYC, alternative Tomasetto for helpful discussions, F Devez and V Ducruit for expert technical assistance. The BAC clone RP11-386F9 was mechanisms to increase TRAF4 expression also exist kindly provided by M Rocchi. This work was supported by since 69% of the tumors examined overexpressed funds from the Institut National de la Sante´ et de la Recherche TRAF4 without alteration of the gene copy number. Me´ dicale, the Association pour la Recherche sur le Cancer Although evidence for a direct oncogenic role of (CH Re´ gnier, contract no. 4801) and the Alliance des TRAF4 has yet to emerge, our results indicate that this Recherches sur le Cancer.

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