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Amjad P Khan,
Thekkelnaycke M Rajendiran,
Bushra Ateeq,
Irfan A Asangani,
Jyoti N Athanikar,
Anastasia K Yocum, Rohit Mehra,
Javed Siddiqui,
Ganesh Palapattu,
John T Wei,
George Michailidis,
Arun Sreekumar,
Arul M Chinnaiyan
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ABSTRACT: Metabolomic profiling of prostate cancer (PCa) progression identified markedly elevated levels of sarcosine (N-methyl glycine) in metastatic PCa and modest but significant elevation of the metabolite in PCa urine. Here, we examine the role of key enzymes associated with sarcosine metabolism in PCa progression. Consistent with our earlier report, sarcosine levels were significantly elevated in PCa urine sediments compared to controls, with a modest area under the receiver operating characteristic curve of 0.71. In addition, the expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), was elevated in PCa tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced in prostate tumors. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine. Accordingly, addition of sarcosine, but not glycine or alanine, induced invasion and intravasation in an in vivo PCa model. In contrast, GNMT knockdown or SARDH overexpression in PCa xenografts inhibited tumor growth. Taken together, these studies substantiate the role of sarcosine in PCa progression.
Neoplasia (New York, N.Y.) 05/2013; 15(5):491-501. · 5.48 Impact Factor
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ABSTRACT: BACKGROUND: Progressive aging- and inflammation-associated fibrosis effectively remodels the extracellular matrix (ECM) to increase prostate tissue stiffness and reduce urethral flexibility, resulting in urinary flow obstruction and lower urinary tract symptoms (LUTS). In the current study, we sought to test whether senescence-accelerated mouse prone (SAMP)6 mice, which were reported to develop prostatic fibrosis, would also develop LUTS, and whether these symptoms would be exacerbated by diet-induced obesity and concurrent Type 2 Diabetes Mellitus (T2DM). METHODS: To accomplish this, SAMP6 and AKR/J background strain mice were fed regular mouse chow, low fat diet chow, or high fat diet chow for 8 months, then subjected to glucose tolerance tests, assessed for plasma insulin levels, evaluated for urinary voiding function, and assessed for lower urinary tract fibrosis. RESULTS: The results of these studies show that SAMP6 mice and AKR/J background strain mice develop diet-induced obesity and T2DM concurrent with urinary voiding dysfunction. Moreover, urinary voiding dysfunction was more severe in SAMP6 than AKR/J mice and was associated with pronounced prostatic and urethral tissue fibrosis. CONCLUSIONS: Taken together, these studies suggest that obesity, T2DM, lower urinary tract fibrosis, and urinary voiding dysfunction are inextricably and biologically linked. Prostate © 2013 Wiley Periodicals, Inc.
The Prostate 03/2013; · 3.48 Impact Factor
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Irfan A Asangani,
Bushra Ateeq,
Qi Cao,
Lois Dodson,
Mithil Pandhi,
Lakshmi P Kunju, Rohit Mehra,
Robert J Lonigro,
Javed Siddiqui,
Nallasivam Palanisamy,
Yi-Mi Wu,
Xuhong Cao,
Jung H Kim,
Meng Zhao,
Zhaohui S Qin,
Mathew K Iyer,
Christopher A Maher,
Chandan Kumar-Sinha,
Sooryanarayana Varambally,
Arul M Chinnaiyan
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ABSTRACT: Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.
Molecular cell 11/2012; · 14.61 Impact Factor
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ABSTRACT: Apoptosis inducing factor (AIF) promotes cell death yet also controls mitochondrial homeostasis and energy metabolism. It is unclear how these activities are coordinated, and the impact of AIF upon human disease, in particular cancer, is not well documented. In this study we have explored the contribution of AIF to the progression of prostate cancer. Analysis of archival gene expression data demonstrated that AIF transcript levels are elevated in human prostate cancer, and we found that AIF protein is increased in prostate tumors. Suppression of AIF expression in the prostate cancer cell lines LNCaP, DU145, and PC3 demonstrated that AIF does not contribute to cell toxicity via a variety of chemical death triggers, and growth under nutrient rich conditions is largely unaffected by AIF ablation. However under growth stress conditions AIF depletion from DU145 and PC3 cell lines led to significant reductions in cell survival and growth that were not observed in LNCaP cells. Moreover AIF-deficient PC3 cells exhibited substantial reduction of tumorigenic growth in vivo. This reduced survival correlated with decreased expression of mitochondrial complex I protein subunits and concomitant changes in glucose metabolism. Finally, restoration of AIF-deficient PC3 cells with AIF variants demonstrated that the enzymatic activity of AIF is required for aggressive growth. Overall these studies show that AIF is an important factor for advanced prostate cancer cells, and that through control of energy metabolism and redox balance the enzymatic activity of AIF is critical for this support.
Journal of Biological Chemistry 11/2012; · 4.77 Impact Factor
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Rui Wang,
Irfan A Asangani,
Balabhadrapatruni V S K Chakravarthi,
Bushra Ateeq,
Robert J Lonigro,
Qi Cao,
Ram-Shankar Mani,
Daniel F Camacho,
Natalie Mcgregor,
Taibriana E W Schumann, [......], Rohit Mehra,
Javed Siddiqui,
Saravana M Dhanasekaran,
Mukesh K Nyati,
Kenneth J Pienta,
Nallasivam Palanisamy,
Lakshmi P Kunju,
Mark A Rubin,
Arul M Chinnaiyan,
Sooryanarayana Varambally
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ABSTRACT: Transcriptional repressors and corepressors play a critical role in cellular homeostasis and are frequently altered in cancer. C-terminal binding protein 1 (CtBP1), a transcriptional corepressor that regulates the expression of tumor sup-pressors and genes involved in cell death, is known to play a role in multiple cancers. In this study, we observed the overexpression and mislocalization of CtBP1 in metastatic prostate cancer and demonstrated the functional signifi-cance of CtBP1 in prostate cancer progression. Transient and stable knockdown of CtBP1 in prostate cancer cells inhibited their proliferation and invasion. Expression profiling studies of prostate cancer cell lines revealed that multiple
Neoplasia 10/2012; · 5.95 Impact Factor
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Rui Wang,
Irfan A Asangani,
Balabhadrapatruni Vsk Chakravarthi,
Bushra Ateeq,
Robert J Lonigro,
Qi Cao,
Ram-Shankar Mani,
Daniel F Camacho,
Natalie McGregor,
Taibriana Ew Schumann, [......], Rohit Mehra,
Javed Siddiqui,
Saravana M Dhanasekaran,
Mukesh K Nyati,
Kenneth J Pienta,
Nallasivam Palanisamy,
Lakshmi P Kunju,
Mark A Rubin,
Arul M Chinnaiyan,
Sooryanarayana Varambally
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ABSTRACT: Transcriptional repressors and corepressors play a critical role in cellular homeostasis and are frequently altered in cancer. C-terminal binding protein 1 (CtBP1), a transcriptional corepressor that regulates the expression of tumor suppressors and genes involved in cell death, is known to play a role in multiple cancers. In this study, we observed the overexpression and mislocalization of CtBP1 in metastatic prostate cancer and demonstrated the functional significance of CtBP1 in prostate cancer progression. Transient and stable knockdown of CtBP1 in prostate cancer cells inhibited their proliferation and invasion. Expression profiling studies of prostate cancer cell lines revealed that multiple tumor suppressor genes are repressed by CtBP1. Furthermore, our studies indicate a role for CtBP1 in conferring radiation resistance to prostate cancer cell lines. In vivo studies using chicken chorioallantoic membrane assay, xenograft studies, and murine metastasis models suggested a role for CtBP1 in prostate tumor growth and metastasis. Taken together, our studies demonstrated that dysregulated expression of CtBP1 plays an important role in prostate cancer progression and may serve as a viable therapeutic target.
Neoplasia (New York, N.Y.) 10/2012; 14(10):905-14. · 5.48 Impact Factor
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ABSTRACT: Recent studies from our group suggest that extracellular matrix (ECM) deposition and fibrosis characterize the peri-urethral prostate tissues of some men suffering from Lower Urinary Tract Symptoms (LUTS) and that fibrosis may be a contributing factor to the etiology of LUTS. Fibrosis can generally be regarded as an errant wound-healing process in response to chronic inflammation, and several studies have shown that the aging prostate tissue microenvironment is rich with inflammatory cells and proteins. However, it is unclear whether these same inflammatory proteins, particularly CXC-type chemokines, can mediate myofibroblast phenoconversion and the ECM deposition necessary for the development of prostatic tissue fibrosis. To examine this, immortalized and primary prostate stromal fibroblasts treated with TGF-β1, CXCL5, CXCL8, or CXCL12 were evaluated morphologically by microscopy, by immunofluorescence and qRT-PCR for αSMA, collagen 1, vimentin, calponin, and tenascin protein and transcript expression, and by gel contraction assays for functional myofibroblast phenoconversion. The results of these studies showed that that immortalized and primary prostate stromal fibroblasts are induced to express collagen 1 and 3 and αSMA gene transcripts and proteins and to undergo complete and functional myofibroblast phenoconversion in response to CXC-type chemokines, even in the absence of exogenous TGF-β1. Moreover, CXCL12-mediated myofibroblast phenoconversion can be completely abrogated by inhibition of the CXCL12 receptor, CXCR4. These findings suggest that CXC-type chemokines, which comprise inflammatory proteins known to be highly expressed in the aging prostate, can efficiently and completely mediate myofibroblast phenoconversion and may thereby promote fibrotic changes in prostate tissue architecture associated with the development and progression of male lower urinary tract dysfunction.
PLoS ONE 01/2012; 7(11):e49278. · 4.09 Impact Factor
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Dan R Robinson,
Shanker Kalyana-Sundaram,
Yi-Mi Wu,
Sunita Shankar,
Xuhong Cao,
Bushra Ateeq,
Irfan A Asangani,
Matthew Iyer,
Christopher A Maher,
Catherine S Grasso, [......],
Xiaojun Jing,
Thomas J Giordano,
Michael S Sabel,
Celina G Kleer,
Nallasivam Palanisamy,
Rachael Natrajan,
Maryou B Lambros,
Jorge S Reis-Filho,
Chandan Kumar-Sinha,
Arul M Chinnaiyan
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ABSTRACT: Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.
Nature medicine 11/2011; 17(12):1646-51. · 27.14 Impact Factor
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Jung H Kim,
Saravana M Dhanasekaran,
John R Prensner,
Xuhong Cao,
Daniel Robinson,
Shanker Kalyana-Sundaram,
Christina Huang,
Sunita Shankar,
Xiaojun Jing,
Matthew Iyer, [......],
Lee Sam,
Catherine Grasso,
Christopher A Maher,
Nallasivam Palanisamy, Rohit Mehra,
Hal D Kominsky,
Javed Siddiqui,
Jindan Yu,
Zhaohui S Qin,
Arul M Chinnaiyan
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ABSTRACT: Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in select prostate tissues and cell lines using MethylPlex-next-generation sequencing (M-NGS). Hidden Markov model-based next-generation sequence analysis identified ∼68,000 methylated regions per sample. While global CpG island (CGI) methylation was not differential between benign adjacent and cancer samples, overall promoter CGI methylation significantly increased from ~12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues, respectively (P-value < 2 × 10(-16)). We found distinct patterns of promoter methylation around transcription start sites, where methylation occurred not only on the CGIs, but also on flanking regions and CGI sparse promoters. Among the 6691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer-specific, including numerous novel DMRs. A novel cancer-specific DMR in the WFDC2 promoter showed frequent methylation in cancer (17/22 tissues, 6/6 cell lines), but not in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested an epigenetic mechanism for alternate transcription start site utilization, and these modifications segregated into distinct regions when present on the same promoter. Finally, we observed differences in repeat element methylation, particularly LINE-1, between ERG gene fusion-positive and -negative cancers, and we confirmed this observation using pyrosequencing on a tissue panel. This comprehensive methylome map will further our understanding of epigenetic regulation in prostate cancer progression.
Genome Research 07/2011; 21(7):1028-41. · 13.61 Impact Factor
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Rohit Mehra,
Chandan Kumar-Sinha,
Sunita Shankar,
Robert J Lonigro,
Xiaojun Jing,
Neena E Philips,
Javed Siddiqui,
Bo Han,
Xuhong Cao,
David C Smith,
Rajal B Shah,
Arul M Chinnaiyan,
Kenneth J Pienta
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ABSTRACT: Bone is the most common metastatic site for prostate cancer, and osseous metastases are the leading cause of morbidity from this disease. Recent autopsy studies prove that 100% of men who die of prostate cancer have bone involvement. Understanding the biology of prostate cancer and its evolution to an incurable androgen-independent phenotype requires an understanding of the genetic and cellular alterations that lead to the seeding and proliferation of tumor foci in bone, as well as the microenvironment in which these metastases arise. No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research.
We show, for the first time, a reproducible methodology to obtain high quality clinical tumor tissues metastatic to the bone. This technique allowed the procurement of viable metastatic tumor tissue from involved bones in 13 recent autopsies conducted at the University of Michigan and analyzed the gene expression of these tissues using real-time PCR and microarrays.
We present here the discovery of nonossified bone metastases from multiple patients with advanced prostate cancer and their subsequent characterization and comparison to nonosseous metastases from the same patients.
This represents a versatile and practical approach that may be employed to characterize the steps in metastasis and the phenotypic characteristics of osseous metastasis of prostate cancer and to profile RNA, DNA, and cDNA from tumor samples metastatic to the bone.
Clinical Cancer Research 06/2011; 17(12):3924-32. · 7.74 Impact Factor
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J Chad Brenner,
Bushra Ateeq,
Yong Li,
Anastasia K Yocum,
Qi Cao,
Irfan A Asangani,
Sonam Patel,
Xiaoju Wang,
Hallie Liang,
Jindan Yu, [......],
Jun Yang,
Scott A Tomlins,
Christopher A Maher,
Kojo S J Elenitoba-Johnson,
Maha Hussain,
Nora M Navone,
Kenneth J Pienta,
Sooryanarayana Varambally,
Felix Y Feng,
Arul M Chinnaiyan
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ABSTRACT: Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
Cancer cell 05/2011; 19(5):664-78. · 25.29 Impact Factor
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Arun Sreekumar,
Laila M Poisson,
Thekkelnaycke M Rajendiran,
Amjad P Khan,
Qi Cao,
Jindan Yu,
Bharathi Laxman, Rohit Mehra,
Robert J Lonigro,
Yong Li, [......],
Gilbert S Omenn,
Debashis Ghoshd,
Subramaniam Pennathur,
Danny C Alexander,
Alvin Berger,
Jeffrey R Shuster,
John T Wei,
Sooryanarayana Varambally,
Christopher Beecher,
Arul M Chinnaiyan
European urology 09/2010; 58(3):e29-30; author reply e31-2. · 7.67 Impact Factor
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Liqun Chen,
Salma Siddiqui,
Swagata Bose,
Benjamin Mooso,
Alfredo Asuncion,
Roble G Bedolla,
Ruth Vinall,
Clifford G Tepper,
Regina Gandour-Edwards,
Xubao Shi,
Xiao-Hua Lu,
Javed Siddiqui,
Arul M Chinnaiyan, Rohit Mehra,
Ralph W Devere White,
Kermit L Carraway,
Paramita M Ghosh
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ABSTRACT: Patients with advanced prostate cancer (PCa) are initially susceptible to androgen withdrawal (AW), but ultimately develop resistance to this therapy (castration-resistant PCa, CRPC). Here, we show that AW can promote CRPC development by increasing the levels of the receptor tyrosine kinase ErbB3 in androgen-dependent PCa, resulting in AW-resistant cell cycle progression and increased androgen receptor (AR) transcriptional activity. CRPC cell lines and human PCa tissue overexpressed ErbB3, whereas downregulation of ErbB3 prevented CRPC cell growth. Investigation of the mechanism by which AW augments ErbB3, using normal prostate-derived pRNS-1-1 cells, and androgen-dependent PCa lines LNCaP, PC346C, and CWR22 mouse xenografts, revealed that the AR suppresses ErbB3 protein levels, whereas AW relieves this suppression, showing for the first time the negative regulation of ErbB3 by AR. We show that AR activation promotes ErbB3 degradation in androgen-dependent cells, and that this effect is mediated by AR-dependent transcriptional upregulation of neuregulin receptor degradation protein-1 (Nrdp1), an E3 ubiquitin ligase that targets ErbB3 for degradation but whose role in PCa has not been previously examined. Therefore, AW decreases Nrdp1 expression, promoting ErbB3 protein accumulation, and leading to AR-independent proliferation. However, in CRPC sublines of LNCaP and CWR22, which strongly overexpress the AR, ErbB3 levels remain elevated due to constitutive suppression of Nrdp1, which prevents AR regulation of Nrdp1. Our observations point to a model of CRPC development in which progression of PCa to castration resistance is associated with the inability of AR to transcriptionally regulate Nrdp1, and predict that inhibition of ErbB3 during AW may impair CRPC development.
Cancer Research 07/2010; 70(14):5994-6003. · 7.86 Impact Factor
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Kyung Park,
Scott A Tomlins,
Kumaran M Mudaliar,
Ya-Lin Chiu,
Raquel Esgueva, Rohit Mehra,
Khalid Suleman,
Sooryanarayana Varambally,
John C Brenner,
Theresa MacDonald,
Abhishek Srivastava,
Ashutosh K Tewari,
Ubaradka Sathyanarayana,
Dea Nagy,
Gary Pestano,
Lakshmi P Kunju,
Francesca Demichelis,
Arul M Chinnaiyan,
Mark A Rubin
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ABSTRACT: TMPRSS2-ERG gene fusions occur in 50% of prostate cancers and result in the overexpression of a chimeric fusion transcript that encodes a truncated ERG product. Previous attempts to detect truncated ERG products have been hindered by a lack of specific antibodies. Here, we characterize a rabbit anti-ERG monoclonal antibody (clone EPR 3864; Epitomics, Burlingame, CA) using immunoblot analysis on prostate cancer cell lines, synthetic TMPRSS2-ERG constructs, chromatin immunoprecipitation, and immunofluorescence. We correlated ERG protein expression with the presence of ERG gene rearrangements in prostate cancer tissues using a combined immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. We independently evaluated two patient cohorts and observed ERG expression confined to prostate cancer cells and high-grade prostatic intraepithelial neoplasia associated with ERG-positive cancer, as well as vessels and lymphocytes (where ERG has a known biologic role). Image analysis of 131 cases demonstrated nearly 100% sensitivity for detecting ERG rearrangement prostate cancer, with only 2 (1.5%) of 131 cases demonstrating strong ERG protein expression without any known ERG gene fusion. The combined pathology evaluation of 207 patient tumors for ERG protein expression had 95.7% sensitivity and 96.5% specificity for determining ERG rearrangement prostate cancer. In conclusion, this study qualifies a specific anti-ERG antibody and demonstrates exquisite association between ERG gene rearrangement and truncated ERG protein product expression. Given the ease of performing IHC versus FISH, ERG protein expression may be useful for molecularly subtyping prostate cancer based on ERG rearrangement status and suggests clinical utility in prostate needle biopsy evaluation.
Neoplasia (New York, N.Y.) 07/2010; 12(7):590-8. · 5.48 Impact Factor
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Juan-Miguel Mosquera, Rohit Mehra,
Meredith M Regan,
Sven Perner,
Elizabeth M Genega,
Gerri Bueti,
Rajal B Shah,
Sandra Gaston,
Scott A Tomlins,
John T Wei,
Michael C Kearney,
Laura A Johnson,
Jeffrey M Tang,
Arul M Chinnaiyan,
Mark A Rubin,
Martin G Sanda
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ABSTRACT: Fusion of the TMPRSS2 prostate-specific gene with the ERG transcription factor is a putatively oncogenic gene rearrangement that is commonly found in prostate cancer tissue from men undergoing prostatectomy. However, the prevalence of the fusion was less common in samples of transurethral resection of the prostate from a Swedish cohort of patients with incidental prostate cancer followed by watchful waiting, raising the question as to whether the high prevalence in prostatectomy specimens reflects selection bias. We sought to determine the prevalence of TMPRSS2-ERG gene fusion among prostate-specific antigen-screened men undergoing prostate biopsy in the United States.
We studied 140 prostate biopsies from the same number of patients for TMPRSS2-ERG fusion status with a fluorescent in situ hybridization assay. One hundred and thirty-four samples (100 cancer and 34 benign) were assessable.
ERG gene rearrangement was detected in 46% of prostate biopsies that were found to have prostate cancer and in 0% of benign prostate biopsies (P < 0.0001). Evaluation of morphologic features showed that cribriform growth, blue-tinged mucin, macronucleoli, and collagenous micronodules were significantly more frequent in TMPRSS2-ERG fusion-positive prostate cancer biopsies than gene fusion-negative prostate cancer biopsies (P < or = 0.04). No significant association with Gleason score was detected. In addition, non-Caucasian patients were less likely to have positive fusion status (P = 0.02).
This is the first prospective North American multicenter study to characterize TMPRSS2-ERG prostate cancer prevalence in a cohort of patients undergoing needle biopsy irrespective of whether or not they subsequently undergo prostatectomy. Our results show that this gene rearrangement is common among North American men who have prostate cancer on biopsy, is absent in benign prostate biopsy, and is associated with specific morphologic features. These findings indicate a need for prospective studies to evaluate the relationship of TMPRSS2-ERG rearrangement with clinical course of screening-detected prostate cancer in North American men, and a need for the development of noninvasive screening tests to detect TMPRSS2-ERG rearrangement.
Clinical Cancer Research 08/2009; 15(14):4706-11. · 7.74 Impact Factor
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Qianben Wang,
Wei Li,
Yong Zhang,
Xin Yuan,
Kexin Xu,
Jindan Yu,
Zhong Chen,
Rameen Beroukhim,
Hongyun Wang,
Mathieu Lupien, [......],
Bo Han,
Arul M Chinnaiyan,
Mark A Rubin,
Lawrence True,
Michelangelo Fiorentino,
Christopher Fiore,
Massimo Loda,
Philip W Kantoff,
X Shirley Liu,
Myles Brown
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ABSTRACT: The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.
Cell 08/2009; 138(2):245-56. · 32.40 Impact Factor
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Daniel R Rhodes,
Bushra Ateeq,
Qi Cao,
Scott A Tomlins, Rohit Mehra,
Bharathi Laxman,
Shanker Kalyana-Sundaram,
Robert J Lonigro,
Beth E Helgeson,
Mahaveer S Bhojani,
Alnawaz Rehemtulla,
Celina G Kleer,
Daniel F Hayes,
Peter C Lucas,
Sooryanarayana Varambally,
Arul M Chinnaiyan
[show abstract]
[hide abstract]
ABSTRACT: Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations. To identify additional opportunities for targeted therapy, we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3,200 microarray experiments. In addition to prioritizing ERBB2, we found AGTR1, the angiotensin II receptor type I, to be markedly overexpressed in 10-20% of breast cancer cases across multiple independent patient cohorts. Validation experiments confirmed that AGTR1 is highly overexpressed, in several cases more than 100-fold. AGTR1 overexpression was restricted to estrogen receptor-positive tumors and was mutually exclusive with ERBB2 overexpression across all samples. Ectopic overexpression of AGTR1 in primary mammary epithelial cells, combined with angiotensin II stimulation, led to a highly invasive phenotype that was attenuated by the AGTR1 antagonist losartan. Similarly, losartan reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts. Taken together, these observations indicate that marked AGTR1 overexpression defines a subpopulation of ER-positive, ERBB2-negative breast cancer that may benefit from targeted therapy with AGTR1 antagonists, such as losartan.
Proceedings of the National Academy of Sciences 07/2009; 106(25):10284-9. · 9.68 Impact Factor
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ABSTRACT: The link between ERG rearrangement and PTEN (phosphatase and tensin homolog deleted on chromosome 10) deletion is unclear in prostate cancer progression. Using fluorescence in situ hybridization, we systematically validated the frequency and distribution of ERG and PTEN aberrations in a cohort of 73 benign prostate tissues, 59 high-grade prostatic intraepithelial neoplasia (HGPIN) foci, 281 localized prostate cancer and 47 androgen-independent metastatic prostate cancer patients. Overall, ERG rearrangement was present in 15% (5/33) of HGPIN, 45% (121/267) of localized cancers and 35% (15/43) of metastases. By contrast, PTEN deletion was identified in 9% (3/33) of HGPIN, 17% (42/251) of localized cancers and 54% (22/41) of metastases, of which 0%, 40% (17/42) and 45% (10/22) were homozygous, respectively. Concomitance of ERG rearrangement and PTEN deletion was observed in a subset of HGPIN. Significantly, association between PTEN deletion and ERG rearrangement was present both in localized cancers (P=0.0008) and metastases (P=0.02). Further, immunohistochemistry revealed significant correlation of decreased PTEN protein expression with PTEN genomic deletion both in localized and metastatic cancer. Of note, ERG aberration, but not PTEN deletion, was consistently identical both in localized cancer and adjacent HGPIN. Similarly, whereas all metastases (41/41, 100%) shared the same ERG status across multiple sites from the same patient, 5% (2/41) of cases showed discordance for PTEN deletion status across multiple sites. Collectively, our data support PTEN deletion as a late genetic event in human prostate cancer, presumably a 'second hit' after ERG rearrangement. PTEN deletion and ERG rearrangement may cooperate, but contribute at different stages, in prostate cancer progression.
Modern Pathology 06/2009; 22(8):1083-93. · 4.79 Impact Factor
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Bo Han, Rohit Mehra,
Khalid Suleman,
Scott A Tomlins,
Lei Wang,
Nishi Singhal,
Katherine A Linetzky,
Nallasivam Palanisamy,
Ming Zhou,
Arul M Chinnaiyan,
Rajal B Shah
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ABSTRACT: Histologic variants of prostate carcinoma account for 5-10% of the disease and are typically seen in association with conventional acinar carcinoma. These variants often differ from the latter in clinical, immunophenotypic, and biologic potential. Recently, recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in a majority of conventional prostate carcinomas. However, the frequency and significance of this critical molecular event is unknown in the histologic variants of prostate carcinoma. Here, we used break-apart fluorescence in situ hybridization to assess TMPRSS2 and ETS aberrations in a series of select histologic variants: foamy gland carcinoma (N=17), ductal adenocarcinoma (N=18), mucinous carcinoma (N=18), and small cell carcinoma (N=7). A histologic variation of acinar adenocarcinoma, demonstrating glomeruloid morphology (N=9), was also investigated. Overall, 55% of histologic variant or variation morphologies demonstrated ETS aberrations (ERG in 54% and ETV1 in 1%). TMPRSS2:ERG fusion was identified in 83% (15/18), 71% (5/7), 50% (9/18), 33% (3/9), and 29% (5/17) of mucinous, small cell, ductal, glomeruloid, and foamy gland prostate carcinomas, respectively. Previously, we reported that 100% of androgen-independent metastatic prostate carcinomas harboring TMPRSS2:ERG gene fusion were associated with interstitial deletion (Edel). Interestingly, ERG rearrangement in small cell carcinomas occurred exclusively through Edel, supporting the notion that TMPRSS2:ERG with Edel is an aggressive molecular subtype. SPINK1, a biomarker expressed exclusively in a subset of ETS negative prostate carcinomas, was expressed in 6% of ETS negative histologic variants, specifically in ductal adenocarcinoma. Notably, 88% (43/49) variant morphologies in this cohort showed concordance of TMPRSS2:ERG fusion with associated conventional acinar type, suggesting that variant morphology is clonally related to the latter. Overall, our data provide insight into the origin, molecular mechanism, and phenotypic association of ETS fusions in histologic variants of prostate carcinoma.
Modern Pathology 06/2009; 22(9):1176-85. · 4.79 Impact Factor
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Rou Wang,
David S Morris,
Scott A Tomlins,
Robert J Lonigro,
Alexander Tsodikov, Rohit Mehra,
Thomas J Giordano,
L Priya Kunju,
Cheryl T Lee,
Alon Z Weizer,
Arul M Chinnaiyan
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ABSTRACT: In bladder cancer, clinical grade and stage fail to capture outcome. We developed a clinically applicable quantitative PCR (QPCR) gene signature to predict progression in non-muscle-invasive bladder cancer. Comparative metaprofiling of 12 DNA microarray data sets (comprising 631 samples and 241,298 probe sets) identified 96 genes, which showed differential expression in seven clinical outcome categories, or were identified as outliers, historic markers, or housekeeping genes. QPCR was done to determine mRNA expression from 96 bladder tumors. Fifty-seven genes differentiated T2 from non-T2 tumors (P < 0.05). Principal components analysis and Cox regression models were used to predict probability of T2 progression for non-T2 patients, placing them into high- and low-risk groups based on their gene expression. At 2 years, high-risk patients exhibited greater T2 progression (45% for high-risk patients versus 12% for low-risk patients; P = 0.003, log-rank test). This difference remained significant within T1 tumors (61% for high-risk patients versus 22% for low-risk patients; P = 0.02) and Ta tumors (29% for high-risk patients versus 0% for low-risk patients; P = 0.03). The best multivariate Cox model included stage and gender, and this signature provided predictive improvement over both (P = 0.002, likelihood ratio test). Immunohistochemistry was done for two genes in the signature not previously described in bladder cancer, ACTN1 and CDC25B, corroborating their up-regulation at the protein level with disease progression. Thus, we identified a 57-gene QPCR panel to help predict progression of non-muscle-invasive bladder cancers and delineate a systematic, generalizable approach to converting microarray data into a multiplex assay for cancer progression.
Cancer Research 05/2009; 69(9):3810-8. · 7.86 Impact Factor
