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Michael Dougan,
Stephanie Dougan,
Joanna Slisz,
Brant Firestone,
Matthew Vanneman,
Dobrin Draganov,
Girija Goyal,
Weibo Li,
Donna Neuberg,
Richard Blumberg,
Nir Hacohen, Dale Porter,
Leigh Zawel,
Glenn Dranoff
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ABSTRACT: The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell-dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.
Journal of Experimental Medicine 09/2010; 207(10):2195-206. · 13.85 Impact Factor
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Rameen Beroukhim,
Craig H Mermel, Dale Porter,
Guo Wei,
Soumya Raychaudhuri,
Jerry Donovan,
Jordi Barretina,
Jesse S Boehm,
Jennifer Dobson,
Mitsuyoshi Urashima, [......],
David G Beer,
Lawrence D True,
Aikou Okamoto,
Scott L Pomeroy,
Samuel Singer,
Todd R Golub,
Eric S Lander,
Gad Getz,
William R Sellers,
Matthew Meyerson
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ABSTRACT: A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.
Nature 02/2010; 463(7283):899-905. · 36.28 Impact Factor
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Alex Gaither, Dale Porter,
Yao Yao,
Jason Borawski,
Guang Yang,
Jerry Donovan,
David Sage,
Joanna Slisz,
Mary Tran,
Christopher Straub,
Tim Ramsey,
Vadim Iourgenko,
Alan Huang,
Yan Chen,
Robert Schlegel,
Mark Labow,
Stephen Fawell,
William R Sellers,
Leigh Zawel
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ABSTRACT: Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNFalpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.
Cancer Research 01/2008; 67(24):11493-8. · 7.86 Impact Factor
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ABSTRACT: Comprehensive genetic, epigenetic and transcriptional analyses of normal and cancerous tissues and cells have yielded many candidate diagnostic, predictive, and prognostic markers and therapeutic targets in human cancer. This article provides a brief overview of SAGE and SAGE-like techniques, highlighting their utility and advantages relative to other genomic technologies for the discovery of drug targets. We also summarize the results of recent comprehensive profiling studies that utilize these methods to provide insights into mechanisms of tumor initiation and progression, to improve our molecular understanding of the tumor microenvironment and to reveal new targets and avenues for therapeutic interventions.
Drug Discovery Today 03/2006; 11(3-4):110-8. · 6.83 Impact Factor
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ABSTRACT: The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchorage-dependent and anchorage-independent cell growth, cell migration, and invasion. Expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1-expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1-mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.
Cancer Research 12/2005; 65(21):9659-69. · 7.86 Impact Factor
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Minna Allinen,
Rameen Beroukhim,
Li Cai,
Cameron Brennan,
Jaana Lahti-Domenici,
Haiyan Huang, Dale Porter,
Min Hu,
Lynda Chin,
Andrea Richardson,
Stuart Schnitt,
William R Sellers,
Kornelia Polyak
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ABSTRACT: Here we describe the comprehensive gene expression profiles of each cell type composing normal breast tissue and in situ and invasive breast carcinomas using serial analysis of gene expression. Based on these data, we determined that extensive gene expression changes occur in all cell types during cancer progression and that a significant fraction of altered genes encode secreted proteins and receptors. Despite the dramatic gene expression changes in all cell types, genetic alterations were detected only in cancer epithelial cells. The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. Thus, chemokines may play a role in breast tumorigenesis by acting as paracrine factors.
Cancer Cell 08/2004; 6(1):17-32. · 26.57 Impact Factor
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ABSTRACT: Cancer is a genetic disease. Genetic events including mutations, chromosomal gains, losses and rearrangements, along with epigenetic alterations, lead to significant transcriptional changes in cancer cells. Changes in the expression of many genes associated with the onset and progression of cancer likely contribute to the cancerous phenotype. SAGE (Serial Analysis of Gene Expression) is an expression profiling method that allows for global, unbiased and quantitative characterisation of transcriptomes. The expression of thousands of genes can be analysed simultaneously without prior knowledge of their sequence, thus leading to the discovery of novel transcripts. In addition to characterising normal and malignant gene expression patterns, SAGE can be used to identify downstream targets of tumour suppressors and oncogenes and further annotate genomes. Comprehensive analyses of expression profiles using SAGE will yield many new diagnostic and prognostic markers as well as therapeutic targets in cancer.
Expert opinion on therapeutic targets 01/2004; 7(6):759-69. · 3.72 Impact Factor
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Dale Porter,
Stanislawa Weremowicz,
Koei Chin,
Pankaj Seth,
Aparna Keshaviah,
Jaana Lahti-Domenici,
Young Kyung Bae,
Constance L Monitto,
Ana Merlos-Suarez,
Jennifer Chan,
Christine M Hulette,
Andrea Richardson,
Cynthia C Morton,
Jeffrey Marks,
Mabel Duyao,
Ralph Hruban,
Edward Gabrielson,
Rebecca Gelman,
Kornelia Polyak
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ABSTRACT: Using serial analysis of gene expression (SAGE), we identified a SAGE tag that was present only in invasive breast carcinomas and their lymph node metastases. The transcript corresponding to this SAGE tag, dermcidin (DCD), encodes a secreted protein normally expressed only in the pons of the brain and sweat glands. Array comparative genomic hybridization, fluorescence in situ hybridization, and immunohistochemical analyses determined that DCD is overexpressed in approximately 10% of invasive breast carcinomas; in some cases its overexpression is coupled with a focal copy number gain of its locus at 12q13.1, and its expression is associated with advanced clinical stage and poor prognosis. Expression of DCD in breast cancer cells promotes cell growth and survival and reduces serum dependency. Putative high- and low-affinity receptors for DCD are present on the cell surface of breast carcinomas and neurons of the brain. Based on these data we hypothesize that DCD may play a role in tumorigenesis by means of enhancing cell growth and survival in a subset of breast carcinomas.
Proceedings of the National Academy of Sciences 10/2003; 100(19):10931-6. · 9.68 Impact Factor
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Dale Porter,
Jaana Lahti-Domenici,
Aparna Keshaviah,
Young Kyung Bae,
Pedram Argani,
Jeffrey Marks,
Andrea Richardson,
Amiel Cooper,
Robert Strausberg,
Gregory J Riggins,
Stuart Schnitt,
Edward Gabrielson,
Rebecca Gelman,
Kornelia Polyak
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ABSTRACT: Gene expression patterns in ductal carcinoma in situ (DCIS), and in invasive, and metastatic breast tumors were determined using serial analysis of gene expression (SAGE). We used mRNA in situ hybridization to examine gene expression at the cellular level and immunohistochemistry on tissue microarrays to determine association between gene expression patterns and histopathologic characteristics of the tumors. We found that that the most dramatic transcriptome change occurs at the normal to DCIS transition, while there is no clear universal "in situ" or "invasive" tumor molecular signature. From the 16,430 transcripts analyzed, we identified only 5 and 11 that were preferentially up-regulated in DCIS and invasive tumors, respectively. The majority of invasive cancer specific SAGE tags correspond to novel genes. The genes we identified may define biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease.
Molecular Cancer Research 04/2003; 1(5):362-75. · 4.29 Impact Factor
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ABSTRACT: To gain insight into the in vivo role of estrogen, we isolated estrogen receptor-positive cells fromnormal human breast tissue using a recombinant adenovirus that expresses green fluorescence protein in response to estrogen. We compared the global gene expression profile of these estrogen receptor-positive cells with that of various normal and cancerous mammary epithelial cells and identified several genes not implicated previously in estrogen signaling. One of these genes, lipocalin 2, is a putative in vivo estrogen target gene and paracrine factor that mediates the growth regulatory effects of estrogen in normal breast epithelium. These results demonstrate that normal and cancerous estrogen receptor-positive cells are distinct at the molecular level and suggest that lipocalin 2 is a new therapeutic target for breast cancer prevention and treatment.
Cancer Research 09/2002; 62(16):4540-4. · 7.86 Impact Factor
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ABSTRACT: We analyzed the expression of high in normal-1 (HIN-1), a putative breast tumor suppressor gene, and uteroglobin related protein-1 (UGRP-1), a homologue of HIN-1, in adult and developing mouse tissues. Highest HIN-1 and UGRP-1 expression is detected in the lung, while lower level HIN-1 expression is also detected in the stomach, heart, small intestine, uterine and mammary glands. The expression of both genes was detected only at E17.5-18.5 and the HIN-1 messenger RNA was localized to the epithelia of the trachea, bronchi, and uterine glands. The expression of HIN-1 is up-regulated during retinoic acid induced differentiation of bronchial epithelial cells. We also identified two putative Drosophila HIN-1 homologues. The expression of HIN-1 is restricted to terminally differentiated airway epithelial cells in vivo and in vitro implicating HIN-1 in the acquisition or maintenance of terminally differentiated epithelial phenotype.
Mechanisms of Development 07/2002; 114(1-2):201-4. · 2.83 Impact Factor
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ABSTRACT: The breast cancer promoting effects of estrogen and the chemopreventive effects of tamoxifen are thought to be mediated by the estrogen receptor, a ligand-dependent transcription factor. Therefore, comprehensive analysis of gene expression profiles following estrogen or tamoxifen treatment may help us better understand the role estrogen plays in tumorigenesis. We utilized SAGE (Serial Analysis of Gene Expression) technology to identify genes regulated by estrogen and tamoxifen in the ZR75-1 estrogen dependent breast cancer cell line. In this manner we have identified several genes that were regulated by estrogen or tamoxifen. Here we report the identification and initial characterization of EIT-6 (Estrogen Induced Tag-6), a novel nuclear protein and a new member of the evolutionarily conserved SM-20 family of growth regulatory immediate-early genes. EIT-6 appears to be a direct transcriptional target of the estrogen receptor and constitutive expression of EIT-6 promotes colony growth in human breast cancer cells. These data indicate that EIT-6 may play a role in estrogen induced cell growth.
Oncogene 02/2002; 21(5):836-43. · 6.37 Impact Factor
