G2Cdb::Gene report

Gene id
G00001863
Gene symbol
MTDH (HGNC)
Species
Homo sapiens
Description
metadherin
Orthologue
G00000614 (Mus musculus)

Databases (7)

Gene
ENSG00000147649 (Ensembl human gene)
92140 (Entrez Gene)
1023 (G2Cdb plasticity & disease)
MTDH (GeneCards)
Literature
610323 (OMIM)
Marker Symbol
HGNC:29608 (HGNC)
Protein Sequence
Q86UE4 (UniProt)

Synonyms (3)

  • 3D3
  • AEG-1
  • LYRIC

Literature (28)

Pubmed - other

  • Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis.

    Emdad L, Lee SG, Su ZZ, Jeon HY, Boukerche H, Sarkar D and Fisher PB

    Department of Neurosurgery and Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.

    Astrocyte-elevated gene-1 (AEG-1) expression is increased in multiple cancers and plays a central role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Additionally, overexpression of AEG-1 protects primary and transformed human and rat cells from serum starvation-induced apoptosis through activation of PI3K/Akt signaling. These findings suggest, but do not prove, that AEG-1 may function as an oncogene. We now provide definitive evidence that AEG-1 is indeed a transforming oncogene and show that stable expression of AEG-1 in normal immortal cloned rat embryo fibroblast (CREF) cells induces morphological transformation and enhances invasion and anchorage-independent growth in soft agar, two fundamental biological events associated with cellular transformation. Additionally, AEG-1-expressing CREF clones form aggressive tumors in nude mice. Immunohistochemistry analysis of tumor sections demonstrates that AEG-1-expressing tumors have increased microvessel density throughout the entire tumor sections. Overexpression of AEG-1 increases expression of molecular markers of angiogenesis, including angiopoietin-1, matrix metalloprotease-2, and hypoxia-inducible factor 1-alpha. In vitro angiogenesis studies further demonstrate that AEG-1 promotes tube formation in Matrigel and increases invasion of human umbilical vein endothelial cells via the PI3K/Akt signaling pathway. Tube formation induced by AEG-1 correlates with increased expression of angiogenesis markers, including Tie2 and hypoxia-inducible factor-alpha, and blocking AEG-1-induced Tie2 with Tie2 siRNA significantly inhibits AEG-1-induced tube formation in Matrigel. Overall, our findings demonstrate that aberrant AEG-1 expression plays a dominant positive role in regulating oncogenic transformation and angiogenesis. These findings suggest that AEG-1 may provide a viable target for directly suppressing the cancer phenotype.

    Funded by: NCI NIH HHS: CA097318, CA134721, R01 CA097318, R01 CA134721; NINDS NIH HHS: NS31492, P01 NS031492

    Proceedings of the National Academy of Sciences of the United States of America 2009;106;50;21300-5

  • Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression.

    Thirkettle HJ, Mills IG, Whitaker HC and Neal DE

    Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK.

    LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-kappaB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.

    Funded by: Cancer Research UK; Medical Research Council: G0500966

    Oncogene 2009;28;41;3663-70

  • Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1.

    Li J, Yang L, Song L, Xiong H, Wang L, Yan X, Yuan J, Wu J and Li M

    Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

    We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (P<0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27Kip1 and p21Cip1 two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer.

    Oncogene 2009;28;36;3188-96

  • Astrocyte elevated gene-1 (AEG-1) is induced by lipopolysaccharide as toll-like receptor 4 (TLR4) ligand and regulates TLR4 signalling.

    Khuda II, Koide N, Noman AS, Dagvadorj J, Tumurkhuu G, Naiki Y, Komatsu T, Yoshida T and Yokochi T

    Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.

    Astrocyte elevated gene-1 (AEG-1) is induced by human immunodeficiency virus 1 (HIV-1) infection and involved in tumour progression, migration and invasion as a nuclear factor-kappaB (NF-kappaB) -dependent gene. The involvement of AEG-1 on lipopolysaccharide (LPS) -induced proinflammatory cytokine production was examined. AEG-1 was induced via NF-kappaB activation in LPS-stimulated U937 human promonocytic cells. AEG-1 induced by LPS subsequently regulated NF-kappaB activation. The prevention of AEG-1 expression inhibited LPS-induced tumour necrosis factor-alpha and prostaglandin E(2) production. The AEG-1 activation was not induced by toll-like receptor ligands other than LPS. Therefore, AEG-1 was suggested to be a LPS-responsive gene and involved in LPS-induced inflammatory response.

    Immunology 2009;128;1 Suppl;e700-6

  • Defining the human deubiquitinating enzyme interaction landscape.

    Sowa ME, Bennett EJ, Gygi SP and Harper JW

    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

    Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.

    Funded by: NIA NIH HHS: AG085011, R01 AG011085, R01 AG011085-16; NIGMS NIH HHS: GM054137, GM67945, R01 GM054137, R01 GM054137-14, R01 GM067945

    Cell 2009;138;2;389-403

  • Astrocyte elevated gene-1 contributes to the pathogenesis of neuroblastoma.

    Lee SG, Jeon HY, Su ZZ, Richards JE, Vozhilla N, Sarkar D, Van Maerken T and Fisher PB

    Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA. sglee@vcu.edu

    Neuroblastoma, derived from neural crest progenitor cells, is the most common extracranial solid tumor of childhood. Astrocyte elevated gene-1 (AEG-1) is a primary mediator of tumor progression and metastasis in several human cancers. In this study, we investigated the potential contribution of AEG-1 in human neuroblastoma pathogenesis. AEG-1 expression was significantly elevated in neuroblastoma patient-derived samples and neuroblastoma cell lines as compared with normal peripheral nerve tissues, normal astrocytes and immortalized melanocytes. Knockdown of AEG-1 by small interfering RNA reduced the tumorigenic properties of highly aggressive neuroblastoma cells. Conversely, over-expression of AEG-1 enhanced proliferation and expression of the transformed state in less aggressive neuroblastoma cells through activation of the phosphatidylinositol 3-kinase-Akt-signaling pathway and stabilization of MYCN. These provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of neuroblastoma and could represent a potential target for therapeutic intervention.

    Funded by: NCI NIH HHS: R01 CA035675; NINDS NIH HHS: P01 NS31492

    Oncogene 2009;28;26;2476-84

  • LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals.

    Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H, Hamdy F, Whitaker HC and Neal DE

    Uro-Oncology Research Group, Cancer Research UK.

    Purpose: LYRIC/AEG-1 has been reported to influence breast cancer survival and metastases, and its altered expression has been found in a number of cancers. The cellular function of LYRIC/AEG-1 has previously been related to its subcellular distribution in cell lines. LYRIC/AEG-1 contains three uncharacterized nuclear localization signals (NLS), which may regulate its distribution and, ultimately, function in cells.

    Immunohistochemistry of a human prostate tissue microarray composed of 179 prostate cancer and 24 benign samples was used to assess LYRIC/AEG-1 distribution. Green fluorescent protein-NLS fusion proteins and deletion constructs were used to show the ability of LYRIC/AEG-1 NLS to target green fluorescent protein from the cytoplasm to the nucleus. Immunoprecipitation and Western blotting were used to show posttranslational modification of LYRIC/AEG-1 NLS regions.

    Results: Using a prostate tissue microarray, significant changes in the distribution of LYRIC/AEG-1 were observed in prostate cancer as an increased cytoplasmic distribution in tumors compared with benign tissue. These differences were most marked in high grade and aggressive prostate cancers and were associated with decreased survival. The COOH-terminal extended NLS-3 (amino acids 546-582) is the predominant regulator of nuclear localization, whereas extended NLS-1 (amino acids 78-130) regulates its nucleolar localization. Within the extended NLS-2 region (amino acids 415-486), LYRIC/AEG-1 can be modified by ubiquitin almost exclusively within the cytoplasm.

    Conclusions: Changes in LYRIC/AEG-1 subcellular distribution can predict Gleason grade and survival. Two lysine-rich regions (NLS-1 and NLS-3) can target LYRIC/AEG-1 to subcellular compartments whereas NLS-2 is modified by ubiquitin in the cytoplasm.

    Funded by: Cancer Research UK; Medical Research Council: G0500966

    Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15;9;3003-13

  • Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis.

    Yu C, Chen K, Zheng H, Guo X, Jia W, Li M, Zeng M, Li J and Song L

    State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, People's Republic of China.

    Astrocyte elevated gene-1 (AEG-1), upregulated in various types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the functional significance of AEG-1 in human esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we showed the expression of AEG-1 was markedly upregulated in esophageal cancer cell lines and surgical ESCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 80 of 168 (47.6%) paraffin-embedded archival ESCC specimens exhibited high levels of AEG-1 expression. Statistical analysis suggested the upregulation of AEG-1 was significantly correlated with the clinical staging of the ESCC patients (P = 0.001), T classification (P = 0.002), N classification (P = 0.034), M classification (P = 0.021) and histological differentiation (P = 0.035) and those patients with high AEG-1 levels exhibited shorter survival time (P < 0.001). Multivariate analysis indicated that AEG-1 expression might be an independent prognostic indicator of the survival of patients with ESCC. Furthermore, we found that ectopic expression of AEG-1 in ESCC cells could significantly enhance cell proliferation and anchorage-independent growth ability. Conversely, silencing AEG-1 by short hairpin RNAi caused an inhibition of cell growth and anchorage-independent growth ability on soft agar. Moreover, we demonstrated that the upregulation of AEG-1 could reduce the expression of p27(Kip1) and induce the expression of cyclin D1 through the AKT/FOXO3a pathway. Our findings suggest that the AEG-1 protein is a valuable marker of ESCC progression and that the upregulation of AEG-1 plays an important role in the development and pathogenesis of human ESCC.

    Carcinogenesis 2009;30;5;894-901

  • Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression.

    Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, Mills AS, Waxman S, Fisher RA, Llovet JM, Fisher PB and Sarkar D

    Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.

    Hepatocellular carcinoma (HCC) is a highly aggressive vascular cancer characterized by diverse etiology, activation of multiple signal transduction pathways, and various gene mutations. Here, we have determined a specific role for astrocyte elevated gene-1 (AEG1) in HCC pathogenesis. Expression of AEG1 was extremely low in human hepatocytes, but its levels were significantly increased in human HCC. Stable overexpression of AEG1 converted nontumorigenic human HCC cells into highly aggressive vascular tumors, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In human HCC, AEG1 overexpression was associated with elevated copy numbers. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 also was found to activate Wnt/beta-catenin signaling via ERK42/44 activation and upregulated lymphoid-enhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for HCC progression. Inhibition studies further demonstrated that activation of Wnt signaling played a key role in mediating AEG1 function. AEG1 also activated the NF-kappaB pathway, which may play a role in the chronic inflammatory changes preceding HCC development. These data indicate that AEG1 plays a central role in regulating diverse aspects of HCC pathogenesis. Targeted inhibition of AEG1 might lead to the shutdown of key elemental characteristics of HCC and could lead to an effective therapeutic strategy for HCC.

    Funded by: NCI NIH HHS: R01 CA 035675, R01 CA035675; NIDDK NIH HHS: N01 DK 92310, R01 DK 076986, R01 DK076986; NINDS NIH HHS: P01 NS 31492, P01 NS031492; NLM NIH HHS: N01DK92310

    The Journal of clinical investigation 2009;119;3;465-77

  • MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.

    Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG and Kang Y

    Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

    Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.

    Funded by: NCI NIH HHS: R01 CA134519, R01 CA134519-01

    Cancer cell 2009;15;1;9-20

  • LYRIC/AEG-1 overexpression modulates BCCIPalpha protein levels in prostate tumor cells.

    Ash SC, Yang DQ and Britt DE

    Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, and The Alpert Medical School, Brown University, 593 Eddy Street, Geo. 362, Providence RI 02903, USA.

    LYRIC/AEG-1 is a unique protein that has been shown to promote tumor cell migration and invasion through activation of the transcription factor NF-kappaB. We performed yeast two-hybrid screening to detect LYRIC/AEG-1 associated proteins, and identified BCCIP, a CDKN1A and BRCA2-associated protein involved in cell cycle regulation and DNA repair. Here, we demonstrate association between LYRIC/AEG-1 and BCCIP in mammalian cells, and define the region of interaction. Co-expression of the two proteins resulted in decreased levels of BCCIPalpha, an effect partially abrogated by proteasome inhibition. A truncated LYRIC/AEG-1 construct lacking the interaction region did not alter BCCIPalpha protein levels. Coincidentally, it was observed that overexpression of BCCIPalpha in DU145 prostate tumor cells induced an apparent neuroendocrine differentiation. In summary, our data suggest LYRIC/AEG-1 is a negative regulator of BCCIPalpha, promoting proteasomal degradation either through direct interaction, or potentially through an indirect mechanism involving downstream effects of the NF-kappaB signaling pathway.

    Funded by: NCRR NIH HHS: P20 RR017695, P20 RR017695-03, RR-P20 RR17695

    Biochemical and biophysical research communications 2008;371;2;333-8

  • Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival.

    Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY, Wu J, Yuan J, Zhang HZ, Zeng MS and Li M

    Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China.

    Purpose: The present study was aimed at clarifying the expression of astrocyte elevated gene-1 (AEG-1), one of the target genes of oncogenic Ha-ras, in breast cancer and its correlation with clinicopathologic features, including the survival of patients with breast cancer.

    The expression of AEG-1 in normal breast epithelial cells, breast cancer cell lines, and in four cases of paired primary breast tumor and normal breast tissue was examined using reverse transcription-PCR and Western blot. Real-time reverse transcription-PCR was applied to determine the mRNA level of AEG-1 in the four paired tissues, each from the same subject. Furthermore, AEG-1 protein expression was analyzed in 225 clinicopathologically characterized breast cancer cases using immunohistochemistry. Statistical analyses were applied to test for the prognostic and diagnostic associations.

    Results: Western blot and reverse transcription-PCR showed that the expression level of AEG-1 was markedly higher in breast cancer cell lines than that in the normal breast epithelial cells at both mRNA and protein levels. AEG-1 expression levels were significantly up-regulated by up to 35-fold in primary breast tumors in comparison to the paired normal breast tissue from the same patient. Immunohistochemical analysis revealed high expression of AEG-1 in 100 of 225 (44.4%) paraffin-embedded archival breast cancer biopsies. Statistical analysis showed a significant correlation of AEG-1 expression with the clinical staging of the patients with breast cancer (P = 0.001), as well as with the tumor classification (P = 0.004), node classification (P = 0.026), and metastasis classification (P = 0.001). Patients with higher AEG-1 expression had shorter overall survival time, whereas patients with lower AEG-1 expression had better survival. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of patients with breast cancer.

    Conclusions: Our results suggest that AEG-1 protein is a valuable marker of breast cancer progression. High AEG-1 expression is associated with poor overall survival in patients with breast cancer.

    Clinical cancer research : an official journal of the American Association for Cancer Research 2008;14;11;3319-26

  • Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1.

    Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ and Fisher PB

    Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York, USA. dsarkar@vcu.edu

    Malignant glioma is a consistently fatal brain cancer. The tumor invades the surrounding tissue, limiting complete surgical removal and thereby initiating recurrence. Identifying molecules critical for glioma invasion is essential to develop targeted, effective therapies. The expression of astrocyte elevated gene-1 (AEG-1) increases in malignant glioma and AEG-1 regulates in vitro invasion and migration of malignant glioma cells by activating the nuclear factor-kappaB (NF-kappaB) signaling pathway. The present studies elucidate the domains of AEG-1 important for mediating its function. Serial NH(2)-terminal and COOH-terminal deletion mutants were constructed and functional analysis revealed that the NH(2)-terminal 71 amino acids were essential for invasion, migration, and NF-kappaB-activating properties of AEG-1. The p65-interaction domain was identified between amino acids 101 to 205, indicating that p65 interaction alone is not sufficient to mediate AEG-1 function. Coimmunoprecipitation assays revealed that AEG-1 interacts with cyclic AMP-responsive element binding protein-binding protein (CBP), indicating that it might act as a bridging factor between NF-kappaB, CBP, and the basal transcription machinery. Chromatin immunoprecipitation assays showed that AEG-1 is associated with the NF-kappaB binding element in the interleukin-8 promoter. Thus, AEG-1 might function as a coactivator for NF-kappaB, consequently augmenting expression of genes necessary for invasion of glioma cells. In these contexts, AEG-1 represents a viable potential target for the therapy of malignant glioma.

    Funded by: NINDS NIH HHS: P01 NS31492

    Cancer research 2008;68;5;1478-84

  • Toward a confocal subcellular atlas of the human proteome.

    Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M and Andersson-Svahn H

    Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology, SE-106 91 Stockholm, Sweden.

    Information on protein localization on the subcellular level is important to map and characterize the proteome and to better understand cellular functions of proteins. Here we report on a pilot study of 466 proteins in three human cell lines aimed to allow large scale confocal microscopy analysis using protein-specific antibodies. Approximately 3000 high resolution images were generated, and more than 80% of the analyzed proteins could be classified in one or multiple subcellular compartment(s). The localizations of the proteins showed, in many cases, good agreement with the Gene Ontology localization prediction model. This is the first large scale antibody-based study to localize proteins into subcellular compartments using antibodies and confocal microscopy. The results suggest that this approach might be a valuable tool in conjunction with predictive models for protein localization.

    Molecular & cellular proteomics : MCP 2008;7;3;499-508

  • Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling.

    Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF and Fisher PB

    Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.

    Astrocyte elevated gene-1 (AEG-1) displays oncogenic properties. Its expression is elevated in diverse neoplastic states and it cooperates with Ha-ras to promote cellular transformation. Overexpression of AEG-1 augments invasion and anchorage-independent growth of transformed cells, while AEG-1 siRNA inhibits Ha-ras-mediated colony formation, supporting a potential functional role in tumorigenesis. Additionally, oncogenic Ha-ras induces AEG-1 expression through the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In the present study, we investigated whether AEG-1 could induce serum-independent cell growth, another property of oncogenes. Overexpression of AEG-1 inhibited serum starvation-induced apoptosis through activation of PI3K-Akt signaling, one of the effector pathways induced by activated Ras. AEG-1 also affected the phosphorylation state of Akt substrates that are implicated in apoptosis suppression, including glycogen synthase kinase 3beta, c-Myc, murine double minute 2, p53, p21/mda-6 and Bad. Additionally, AEG-1 blocked the activity of serum starvation-induced caspases. Taken together, these observations provide evidence that AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras and may perform a central role in Ha-ras-mediated carcinogenesis. Activation of survival pathways may be one mechanism by which AEG-1 exerts its oncogenic properties.

    Funded by: NINDS NIH HHS: 5 P01 NS31492

    Oncogene 2008;27;8;1114-21

  • Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity.

    Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Place RF, Pookot D, Majid S, Igawa M and Dahiya R

    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA.

    Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis.

    Funded by: NCI NIH HHS: R01CA101844, R01CA108612, R01CA111470; NIA NIH HHS: R01AG021418; NIDDK NIH HHS: T32DK07790

    Oncogene 2007;26;55;7647-55

  • Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration.

    Emdad L, Sarkar D, Su ZZ, Lee SG, Kang DC, Bruce JN, Volsky DJ and Fisher PB

    Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.

    Tumor progression and metastasis are complex processes involving intricate interplay among multiple gene products. Astrocyte elevated gene (AEG)-1 was cloned as an human immunodeficiency virus (HIV)-1-inducible and tumor necrosis factor-alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes (PHFA) by a rapid subtraction hybridization approach. AEG-1 down-regulates the expression of the glutamate transporter EAAT2; thus, it is implicated in glutamate-induced excitotoxic damage to neurons as evident in HIV-associated neurodegeneration. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells, and AEG-1 cooperates with Ha-ras to augment the transformed phenotype of normal immortal cells. Moreover, AEG-1 is overexpressed in >95% of human malignant glioma samples when compared with normal human brain. Overexpression of AEG-1 increases and siRNA inhibition of AEG-1 decreases migration and invasion of human glioma cells, respectively. AEG-1 contains a lung-homing domain facilitating breast tumor metastasis to lungs. These findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Our recent observations indicate that AEG-1 exerts its effects by activating the nuclear factor kappa B (NF-kappaB) pathway and AEG-1 is a downstream target of Ha-ras and plays an important role in Ha-ras-mediated tumorigenesis. These provocative findings are intensifying interest in AEG-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. In this review, we discuss the cloning, structure and function(s) of AEG-1 and provide recent insights into the diverse actions and intriguing properties of this molecule.

    Funded by: NCI NIH HHS: R01 CA035675, R01 CA035675-19, R01 CA035675-20, R01 CA35675; NIDA NIH HHS: R01 DA017618; NINDS NIH HHS: P01 NS031492, P01 NS031492-110007, P01 NS031492-14, P01 NS31492

    Pharmacology & therapeutics 2007;114;2;155-70

  • Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc.

    Lee SG, Su ZZ, Emdad L, Sarkar D and Fisher PB

    Department of Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.

    It is well established that Ha-ras and c-myc genes collaborate in promoting transformation, tumor progression, and metastasis. However, the precise mechanism underlying this cooperation remains unclear. In the present study, we document that astrocyte elevated gene-1 (AEG-1) is a downstream target molecule of Ha-ras and c-myc, mediating their tumor-promoting effects. AEG-1 expression is elevated in diverse neoplastic states, it cooperates with Ha-ras to promote transformation, and its overexpression augments invasion of transformed cells, demonstrating its functional involvement in Ha-ras-mediated tumorigenesis. We now document that AEG-1 expression is markedly induced by oncogenic Ha-ras, activating the phosphatidylinositol 3-kinase signaling pathway that augments binding of c-Myc to key E-box elements in the AEG-1 promoter, thereby regulating AEG-1 transcription. In addition, Ha-ras-mediated colony formation is inhibited by AEG-1 siRNA. This is a demonstration that Ha-ras activation of a tumor-promoting gene is regulated directly by c-Myc DNA binding via phosphatidylinositol 3-kinase signaling, thus revealing a previously uncharacterized mechanism of Ha-ras-mediated oncogenesis through AEG-1.

    Funded by: NCI NIH HHS: R01 CA035675, R01 CA35675; NINDS NIH HHS: P01 NS031492, P01 NS31492

    Proceedings of the National Academy of Sciences of the United States of America 2006;103;46;17390-5

  • Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.

    Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P and Mann M

    Center for Experimental BioInformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark.

    Cell signaling mechanisms often transmit information via posttranslational protein modifications, most importantly reversible protein phosphorylation. Here we develop and apply a general mass spectrometric technology for identification and quantitation of phosphorylation sites as a function of stimulus, time, and subcellular location. We have detected 6,600 phosphorylation sites on 2,244 proteins and have determined their temporal dynamics after stimulating HeLa cells with epidermal growth factor (EGF) and recorded them in the Phosida database. Fourteen percent of phosphorylation sites are modulated at least 2-fold by EGF, and these were classified by their temporal profiles. Surprisingly, a majority of proteins contain multiple phosphorylation sites showing different kinetics, suggesting that they serve as platforms for integrating signals. In addition to protein kinase cascades, the targets of reversible phosphorylation include ubiquitin ligases, guanine nucleotide exchange factors, and at least 46 different transcriptional regulators. The dynamic phosphoproteome provides a missing link in a global, integrative view of cellular regulation.

    Cell 2006;127;3;635-48

  • Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis.

    Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K and Fisher PB

    Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.

    Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor kappaB (NF-kappaB), a TNF-alpha downstream signaling component, is associated with several human illnesses, including cancer, and NF-kappaB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-kappaB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-kappaB. The NF-kappaB activation induced by AEG-1 corresponded with degradation of IkappaBalpha and nuclear translocation of p65 that resulted in the induction of NF-kappaB downstream genes. Infection with an adenovirus expressing the mt32IkappaBalpha superrepressor (Ad.IkappaBalpha-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-alpha treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-kappaB. Our findings suggest that activation of NF-kappaB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.

    Funded by: NINDS NIH HHS: P01 NS 31492

    Cancer research 2006;66;3;1509-16

  • Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1.

    Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ and Fisher PB

    Hallym University, Ilsong Institute of Life Science, 1605-4, Kwanyang-dong, Anyang, Kyeonggi-do, Republic of Korea.

    We presently describe the full-length cloning and functional characterization of an HIV-1-inducible gene, astrocyte elevated gene (AEG)-1. Additionally, a novel method is outlined for producing tag-free recombinant protein in a baculovirus system and its use in producing AEG-1 protein. AEG-1 mRNA is expressed ubiquitously with higher expression in tissues containing muscular actin and its expression is increased in astrocytes infected with HIV-1 or treated with gp120 or tumor necrosis factor (TNF)-alpha. The mRNA encodes a single pass transmembrane protein of predicted molecular mass of 64-kDa and pI 9.3 that predominantly localizes in the endoplasmic reticulum and perinuclear region. Ectopic expression of AEG-1 inhibits excitatory amino acid transporter 2 (EAAT2) promoter activity with the potential to promote glutamate excitotoxicity and consequently HIV-1-associated dementia (HAD). AEG-1 expression is elevated in subsets of breast carcinomas, malignant gliomas and melanomas and it synergizes with oncogenic Ha-ras to enhance soft agar colony forming ability of non-tumorigenic immortalized melanocytes, documenting its tumor promoting activity. AEG-1 may affect tumor progression in multiple cell lineages by augmenting expression of the transformed phenotype and/or by inducing glutamate excitotoxicity in malignant glioma. In these contexts, an HIV-1-inducible gene, AEG-1, may contribute to multiple brain abnormalities, including HAD and tumor formation, by both common and distinct mechanisms.

    Funded by: NIGMS NIH HHS: GM068488; NINDS NIH HHS: NS31492, P01 NS031492

    Gene 2005;353;1;8-15

  • Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells.

    Britt DE, Yang DF, Yang DQ, Flanagan D, Callanan H, Lim YP, Lin SH and Hixson DC

    Department of Medicine, Rhode Island Hospital/Brown University, Providence, RI 02903, USA. Deborah_Britt@brown.edu

    Tight junctions (TJ) are multiprotein complexes that function to regulate paracellular transport of molecules through epithelial and endothelial cell layers. Many new tight junction-associated proteins have been identified in the past few years, and their functional roles and interactions have just begun to be elucidated. In this paper, we describe a novel protein LYsine-RIch CEACAM1 co-isolated (LYRIC) that is widely expressed and highly conserved between species. LYRIC has no conserved domains that would indicate function and does not appear to be a member of a larger protein family. Data from analysis of rat and human tissue sections and cell lines show that LYRIC colocalizes with tight junction proteins ZO-1 and occludin in polarized epithelial cells, suggesting that LYRIC is part of the tight junction complex. LYRIC dissociates from ZO-1 when junctional complexes are disrupted, and as tight junctions reform, ZO-1 relocalizes before LYRIC. These results suggest that LYRIC is most likely not a structural component required for TJ formation, but rather is recruited during the maturation of the tight junction complex.

    Funded by: NCI NIH HHS: CA42714; NCRR NIH HHS: P20 RR17695

    Experimental cell research 2004;300;1;134-48

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Metadherin, a cell surface protein in breast tumors that mediates lung metastasis.

    Brown DM and Ruoslahti E

    Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 USA.

    We used a phage expression library of cDNAs from metastatic breast carcinoma to identify protein domains that bind to the vasculature of the lung, a frequent site of breast cancer metastasis. We found that one protein domain selectively targeted phage as well as cells to the lung. This domain is part of the protein metadherin, shown by gene expression profiling to be overexpressed in metastatic breast cancer. Immunostaining revealed that metadherin is overexpressed in breast cancer tissue and breast tumor xenografts. Antibodies reactive to the lung-homing domain of metadherin and siRNA-mediated knockdown of metadherin expression in breast cancer cells inhibited experimental lung metastasis, indicating that tumor cell metadherin mediates localization at the metastatic site.

    Funded by: NCI NIH HHS: CA 30199, P01 CA 82713, T32 CA 09579

    Cancer cell 2004;5;4;365-74

  • 3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus.

    Sutherland HG, Lam YW, Briers S, Lamond AI and Bickmore WA

    MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK. Heidi.Sutherland@hgu.mrc.ac.uk

    We previously performed a gene-trap screen in mouse cells with particular focus on clones in which the trapped protein-reporter fusions localise to compartments of the nucleus. Here we describe one such gene-trap line in which the fusion protein showed a unique, patchy distribution at the nuclear periphery. We have cloned the endogenous mouse and human cDNAs encoding the protein trapped in the F9/3D3 cell line. The predicted proteins (64 kDa) encoded by this novel gene are highly conserved and similar to an unpublished rat protein in sequence databases called p80 or lyric. The amino acid sequence of 3D3/lyric indicates that it may be a type-1b membrane protein with a single transmembrane domain (TMD). Antibodies against the endogenous protein recognise multiple isoforms, consistent with multiple 3D3/lyric mRNAs detected by Northern blot analysis. Subcellular fractionation and immunostaining show that 3D3/lyric is located not only principally in the endoplasmic reticulum (ER), but also in the nuclear envelope (NE), which is contiguous with this compartment. Furthermore, 3D3/lyric is also found in the nucleolus and is therefore a rare example of a protein that suggests a possible connection between this compartment and the endoplasmic reticulum.

    Experimental cell research 2004;294;1;94-105

  • Complete sequencing and characterization of 21,243 full-length human cDNAs.

    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T and Sugano S

    Helix Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan.

    As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

    Nature genetics 2004;36;1;40-5

  • Gene expression profiling predicts clinical outcome of breast cancer.

    van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R and Friend SH

    Division of Diagnostic Oncology, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.

    Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

    Nature 2002;415;6871;530-6

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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