I A Sesterhenn

Rajiv Gandhi Cancer Institute & Research Centre, New Dilli, NCT, India

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Publications (235)751.24 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: The prostate transmembrane protein androgen induced 1 (PMEPA1) gene is highly expressed in prostate epithelial cells and is a direct transcriptional target for the androgen receptor (AR). AR protein levels are controlled by the AR-PMEPA1 negative feedback loop through NEDD4-E3 ligase. Reduced expression of PMEPA1 observed in prostate tumors, suggests that loss of PMEPA1 may play critical roles in prostate tumorigenesis. This study focuses on epigenetic mechanisms of reduced PMEPA1 expression in the cancer of the prostate (CaP). Benign (n = 77) and matched malignant (n = 77) prostate epithelial cells were laser capture micro-dissected from OCT embedded frozen prostate sections from 42 Caucasian American (CA) and 35 African American (AA) cases. Purified DNA specimens were analyzed for CpG methylation of the PMEPA1 gene. PMEPA1 mRNA expression levels were evaluated by qRT-PCR. Analysis of PMEPA1 methylation and mRNA expression in the same tumor cell populations indicated a significant inverse correlation between mRNA expression and methylation in CaP (P = 0.0115). We noted higher frequency of CpG methylation within the evaluated first intronic region of the PMEPA1 gene in prostate tumors of CA men as compared with AA. In CaP cell lines, PMEPA1 expression was induced and AR protein levels were diminished in response to treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (decitabine). Cell culture-based studies demonstrated that decitabine restores PMEPA1 expression in AR-positive CaP cell lines. This report reveals the potential role of PMEPA1 gene methylation in the regulation of AR stability. Thus, downregulation of PMEPA1 may result in increased AR protein levels and function in CaP cells, contributing to prostate tumorigenesis.
    Epigenetics: official journal of the DNA Methylation Society 04/2014; 9(6). · 4.58 Impact Factor
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    ABSTRACT: Background:Approximately half of the prostate carcinomas are characterized by a chromosomal rearrangement fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the role and impact of the ERG rearrangement and protein expression on the progression to castration-resistant (CR) disease.Methods:We used a tissue microarray (TMA) constructed from 114 hormone naive (HN) and 117 CR PCs. We analyzed the ERG rearrangement status by fluorescence in situ hybridization and the expression profiles of ERG, androgen receptor (AR) and the proliferation marker Ki67 by immunohistochemistry.Results:Nearly half of the PC tissue specimens (HN: 38%, CR: 46%) harbored a TMPRSS2-ERG gene fusion. HN PCs with positive translocation status showed increased tumor cell proliferation (P<0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in HN and CR PCs (both P<0.0001). Remarkably, the study revealed a subgroup (26%) of CR PCs with ERG rearrangement but without any detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and androgen-regulated serum PSA (both P<0.05).Conclusions:In this study, we identified a subgroup of ERG-rearranged CR PCs without detectable ERG protein expression. Our results suggest that this subgroup could represent CR PCs with a dispensed AR pathway. These tumors might represent a thus far unrecognized subset of patients with AR-independent CR PC who may not benefit from conventional therapy directed against the AR pathway.Prostate Cancer and Prostatic Disease advance online publication, 28 January 2014; doi:10.1038/pcan.2013.62.
    Prostate cancer and prostatic diseases 01/2014; · 2.10 Impact Factor
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    ABSTRACT: Background:To determine whether prostate cancers detected in the anterior vs posterior zones impact clinicopathological features and patient outcomes. This information could potentially affect clinical management.Methods:A retrospective pathological review of 1528 radical prostatectomy specimens submitted between 1989 and 2011 was completed. Specimens were characterized as anterior zone vs posterior zone based on index tumor and predominant tumor volume location. The chi-square test was used to determine associations between tumor location and categorical patient features. Kaplan-Meier unadjusted analysis was used to compare biochemical recurrence-free and overall survival.Results:Tumors occurred predominantly in the anterior location in 155 (10.1%) of specimens. There was no difference between mean age, body mass index, racial distribution, family history, number of previous biopsies, clinical Gleason sum or pathological stage in the two groups. Fewer patients had clinically palpable disease in the anterior tumor group, 28.8% vs 40.7% (P=0.0150). Pretreatment PSA was lower in the anterior tumor group. Total tumor volume did differ with anterior tumors having a mean 8.3 cc vs 5.6 cc (P<0.0001) size and a higher incidence of positive margins (P=0.0008). There were no differences in biochemical recurrence-free or overall survival.Conclusions:Despite the potential for adverse pathological features in anterior-based disease, there appears to be no demographic predilection, notable delay in diagnosis or significant difference in survival outcomes.Prostate Cancer and Prostatic Disease advance online publication, 3 December 2013; doi:10.1038/pcan.2013.54.
    Prostate cancer and prostatic diseases 12/2013; · 2.10 Impact Factor
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    ABSTRACT: Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression. Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA. We identified 1,196 and 2,190 unique proteins stratified by ERG status from prostate tumors and VCaP cells, respectively. Comparative analysis of these two proteomes identified 330 concordantly regulated proteins characterizing enrichment of pathways modulating cytoskeletal and actin reorganization, cell migration, protein biosynthesis, and proteasome and ER-associated protein degradation. ERPs unique for ERG (+) tumors reveal enrichment for cell growth and survival pathways while proteasome and redox function pathways were enriched in ERPs unique for ERG (-) tumors. Meta-analysis of ERPs against CaP gene expression data revealed that Myosin VI and Monoamine oxidase A were positively and negatively correlated to ERG expression, respectively. This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets. Prostate 9999: XX-XX, 2013. © 2013 Wiley Periodicals, Inc.
    The Prostate 09/2013; · 3.84 Impact Factor
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    ABSTRACT: ERG oncogene fusions (predominantly TMPRSS2-ERG) represent the most common (50-70% frequency) and validated prostate cancer (CaP) genome alteration in the Western countries. A common TMPRSS2-ERG fusion type leads to the androgen dependent tumor cell specific expression of the TMPRSS2-ERG fusion transcript and amino terminally truncated ERG oncoprotein. CaP prevalence and aggressiveness, as well as genomic alterations vary in different geographic locations in the world. Recent studies from our group highlighted significantly lower frequency of ERG alterations in prostate index tumors of African American men (~30%) in comparison to Caucasian Americans (~60%). Further, much lower frequencies (10 -25%) of ERG alterations have been reported in studies from China and Japan. There is no study on ERG alterations in CaP patients from India, representing a significant portion of the world male population. This study focuses on the frequency of ERG oncoprotein expression in CaP patients from India. De-identified formalin-fixed paraffin-embedded (FFPE) specimens from radical prostatectomy (RP) specimens of 51 patients from the Rajiv Gandhi Cancer Institute and Research Centre (RGCI), New Delhi, India, were analyzed for ERG alterations. The ERG oncoprotein expression as a surrogate of ERG gene fusions was analyzed by using a highly specific ERG monoclonal antibody (9FY). TMPRSS2-ERG fusion was assessed by fluorescent in situ hybridization (FISH) assays using the break-apart ERG probes. Specimens reflecting prior hormonal treatment, or lacking any tumor content, were excluded from the analyses. Of the thirty evaluable specimens, ERG positive tumors were present in 8 cases (27%) and one tumor specimen exhibited rare ERG positive cells. None of the benign glands were positive for ERG supporting previous studies showing complete specificity of the ERG oncoprotein for detection of tumors cells in prostate. Frequency of ERG oncoprotein expression is much lower in CaP patients from India in comparison to higher frequency of ERG alterations noted in Western countries. ERG frequency in Indian CaP is similar to observations from Japan and China. Since ERG oncogenic activation is a promising biomarker and therapeutic target for CaP, careful evaluation of ERG is needed in CaP patients from different parts of the world.
    Journal of Cancer. 01/2013; 4(6):468-72.
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    ABSTRACT: To systematically evaluate the ETS-related gene (ERG) alterations in the multifocal tumor context using whole-mount prostatectomy specimens from African and Caucasian American patients matched for age, pathologic grade and stage. Oncogenic activation of the ERG is the most common early genomic alteration in patients with prostate cancer (CaP) in Western countries. However, ERG alterations have not been systematically examined in African American patients with a known greater risk of CaP incidence and mortality. ERG oncoprotein expression was analyzed in 91 Caucasian and 91 African American patients with CaP, who were matched for age, Gleason score, and pathologic stage. A unique aspect of the present study was the evaluation of ERG in whole-mount prostatectomy sections, minimizing sampling bias and allowing the careful assessment of the ERG in the multifocal tumor context of CaP. The frequency of ERG-positive prostate tumors was significantly greater among Caucasian Americans than among African Americans when assessed in all tumor foci (41.9% vs 23.9%, P < .0001). A markedly greater frequency of ERG oncoprotein expression was noted between the index tumors of the Caucasian Americans (63.3%) and those of the African Americans (28.6%). Also, in the African American patients, the higher grade index tumors were predominantly ERG negative. ERG typing of CaP established a major difference between the index tumors of Caucasian and African American patients. ERG-negative index tumors might indicate a less favorable outcome for African American patients. The results of the present study underscore that typing of CaP for the ERG could enhance our understanding of the biologic differences between the examined ethnic groups.
    Urology 08/2012; 80(4):749-53. · 2.42 Impact Factor
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    ABSTRACT: Oncogenic activation of ERG resulting from gene fusion is present in over half of all patients with prostate cancer in Western countries. Although the underlying genetic mechanisms have been extensively studied, evaluation of the ERG oncoprotein--the translational product of ERG gene fusions--has just begun. The robust correlation between ERG oncoprotein detection and gene fusion status enables rapid characterization of this protein in large patient cohorts. Recent studies have focused on characterizing the ERG oncoprotein and determining its potential role in the diagnosis and biological stratification of prostate cancer.
    Nature Reviews Urology 02/2012; 9(3):131-7. · 4.79 Impact Factor
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    ABSTRACT: Neural-cadherin is a member of the cadherin gene family encoding the N-cadherin protein that mediates cell adhesion. N-cadherin is a marker of Sertoli cells and is also expressed in germ cells of varying stages of maturation. The purpose of this study was to determine the presence and distribution of this protein by immunohistochemistry in 105 germ cell tumors of both single and mixed histological types and 12 gonadal stromal tumors. Twenty-four germ cell tumors consisted of one cell type and the remaining were mixed. Of the 23 seminomas in either pure or mixed tumors, 74% were positive. Two spermatocytic seminomas were positive. Of the 83 cases with yolk sac tumor, 99% were positive for N-cadherin. The teratomas were positive in 73% in neuroectodermal and / or glandular components. In contrast, 87% of embryonal carcinomas did not express N-cadherin. Only 17% of the syncytiotrophoblastic cells were positive for N-cadherin. In conclusion, N-cadherin expression is very helpful in the identification of yolk sac tumors. In addition to glypican-3 and Sal-like protein 4, N-cadherin can be beneficial for the diagnosis and classification of this subtype of testicular germ cell tumor. Nine of the 12 gonadal stromal tumors were positive to a variable extent.
    Journal of Cancer. 01/2012; 3:381-9.
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    ABSTRACT: The majority of prostate cancers (CaP) are detected in early stages with uncertain prognosis. Therefore, an intensive effort is underway to define early predictive markers of CaP with aggressive progression characteristics.
    Prostate cancer and prostatic diseases 12/2011; · 2.10 Impact Factor
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    ABSTRACT: The majority of prostate cancers (CaP) are detected in early stages with uncertain prognosis. Therefore, an intensive effort is underway to define early predictive markers of CaP with aggressive progression characteristics. In order to define such prognostic markers, we performed comparative analyses of transcriptomes of well- and poorly differentiated (PD) tumor cells from primary tumors of patients (N=40) with 78 months of mean follow-up after radical prostatectomy. Validation experiments were carried out at transcript level by quantitative real-time reverse transcriptase-PCR (RT-PCR) (N=110) and at protein level by immunohistochemistry (N=53) in primary tumors from an independent patient cohort. Association of a biochemical network of 12 genes with SPARC gene as a central node was highlighted with PD phenotype. Of note, there was remarkable enrichment of NKXH_NKXH_HOX composite regulatory elements in the promoter of the genes in this network suggesting a biological significance of this gene-expression regulatory mechanism in CaP progression. Further, quantitative expression analyses of SPARC mRNA in primary prostate tumor cells of 110 patients validated the association of SPARC expression with poor differentiation and higher Gleason score. Most significantly, higher SPARC protein expression at the time of prostatectomy was associated with the subsequent development of metastasis (P=0.0006, AUC=0.803). In summary, we propose that evaluation of SPARC in primary CaP has potential as a prognostic marker of metastatic progression.
    Prostate cancer and prostatic diseases 11/2011; 15(2):150-6. · 2.10 Impact Factor
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    ABSTRACT: ERG, an ETS family transcription factor, is known to be expressed in endothelial cells, and oncogenic ERG gene fusions occur in subsets of prostatic carcinoma, acute myeloid leukemia, and Ewing sarcoma. In this study, we immunohistochemically investigated nuclear ERG expression using a new monoclonal antibody, CPDR ERG-MAb, that is highly specific for detecting ERG protein and ERG-expressing prostate carcinomas. A broad range of vascular endothelial (n = 250), other mesenchymal (n = 973), and epithelial tumors (n = 657) was examined to determine the use of ERG immunohistochemistry in surgical pathology. Only immunostains with ERG-positive normal endothelia (internal control) were considered valid, and only nuclear staining was considered to be positive. In adult tissues, ERG was restricted to endothelial cells and to a subset of bone marrow precursors, but early fetal mesenchyme and subpopulations of fetal cartilage were also positive. In vascular tumors, ERG was expressed in endothelia of all hemangiomas and lymphangiomas, and typically extensively expressed in 96 of 100 angiosarcomas, 42 of 43 epithelioid hemangioendotheliomas, and all 26 Kaposi sarcomas. Among nonvascular mesenchymal tumors, only blastic extramedullary myeloid tumors (7 of 10) and rare Ewing sarcomas (2 of 29) were positive. Among epithelial tumors, 30 of 66 prostatic adenocarcinomas showed focal-to-extensive ERG positivity, with no immunoreactivity in the normal prostate. Other carcinomas and epithelial tumors (n = 643) were ERG negative, with the exception of 1 of 42 large cell undifferentiated pulmonary carcinomas and 1 of 27 mesotheliomas, each of which showed focal nuclear ERG positivity. On the basis of the above observations, ERG is a highly specific new marker for benign and malignant vascular tumors. Among epithelial tumors, ERG shows a great promise as a marker to identify prostatic carcinoma in both primary and metastatic settings.
    The American journal of surgical pathology 03/2011; 35(3):432-41. · 4.06 Impact Factor
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    ABSTRACT: Androgen dependent induction of the ETS related gene (ERG) expression in more than half of all prostate cancers results from gene fusions involving regulatory sequence of androgen regulated genes (i.e. TMPRSS2, SLC45A3 and NDRG1) and protein coding sequence of the ERG. Emerging studies in experimental models underscore the functions of ERG in prostate tumorigenesis. However, biological and biochemical functions of ERG in prostate cancer (CaP) remain to be elucidated. This study suggests that ERG activation plays a role in prostaglandin signaling because knockdown of ERG expression in TMPRSS2-ERG fusion containing CaP cells leads to altered levels of the 15-hydroxy-prostaglandin dehydrogenase (HPGD), a tumor suppressor and prostaglandin catabolizing enzyme, and prostaglandin E2 (PGE2) . We demonstrate that HPGD expression is regulated by the binding of the ERG protein to the core promoter of this gene. Moreover, prostaglandin E2 dependent cell growth and urokinase-type plasminogen activator (uPA) expression are also affected by ERG knockdown. Together, these data imply that the ERG oncoprotein in CaP cells positively influence prostaglandin mediated signaling, which may contribute to tumor progression.
    Cancer biology & therapy 02/2011; 11(4):410-7. · 3.29 Impact Factor
  • Journal of Urology - J UROL. 01/2011; 185(4).
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Journal of Urology - J UROL. 01/2011; 185(4).
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
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    ABSTRACT: Alterations of chromosome 8, including amplification at 8q24 harboring the C-MYC oncogene, have been noted as one of the most common chromosomal abnormalities in prostate cancer (CaP) progression. However, the frequency of C-MYC alterations in CaP has remained uncertain. A recent study, using a new anti-MYC antibody, described prevalent upregulation of nuclear C-MYC protein expression as an early oncogenic alteration in CaP. Further, we have recently reported regulation of C-MYC expression by ERG and a significant correlation between C-MYC overexpression and TMPRSS2-ERG fusion in early stage CaP. These emerging data suggest that increased C-MYC expression may be a critical and early oncogenic event driving CaP progression. In this study, we assessed whether C-MYC mRNA overexpression in primary prostate tumors was predictive of more aggressive tumor or disease progression. Our approach was to quantitatively determine C-MYC mRNA expression levels in laser capture micro-dissected tumor cells and matched benign epithelial cells in a radical prostatectomy cohort with long follow-up data available. On the basis of our results, we conclude that elevated C-MYC expression in primary prostate tumor is biologically relevant and may be a predictor of future biochemical recurrence.
    Prostate cancer and prostatic diseases 12/2010; 13(4):311-5. · 2.10 Impact Factor
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    ABSTRACT: The objective of this study was to assess the incidence of circulating tumor cells (CTCs) in prostate cancer patients with low-volume tumors (less than 0.5 cc) after radical prostatectomy (RP). Blood samples were collected from 64 RP patients to assess the incidence of CTCs following RP. The specimens were processed by whole-mount section. Clinicopathological data (e.g. patient age, race, specimen weight, tumor volume, grade, stage and surgical margin status) and follow-up PSA data were compared to CTC status. Of the 64 RP patients, nine had 'low-volume prostate cancer'. Seven of these patients had detectable levels of CTCs. In two of the seven patients with detectable CTCs, PSA elevation was also observed. Isolation and detection of circulating epithelial cells is possible in low-volume prostate cancer patients. In the setting of low-volume prostate cancer, CTCs may be associated with the presence of detectable PSA levels. However, the detection of CTCs did not predict PSA failure.
    Pathology International 10/2010; 60(10):667-72. · 1.72 Impact Factor
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    ABSTRACT: Gene fusions prevalent in prostate cancer (CaP) lead to the elevated expression of the ERG proto-oncogene. ERG activation present in 50-70% of prostate tumors underscores one of the most common oncogenic alterations in CaP. Despite numerous reports of gene fusions and mRNA expression, ERG oncoprotein status in CaP still remains to be defined. Furthermore, development of ERG protein-based assays may provide a new dimension to evaluation of gene fusions involving diverse androgen-regulated promoters and the ERG protein-coding sequence. Through exhaustive evaluations of 132 whole-mount prostates (261 tumor foci and over 200 000 benign glands) for the ERG oncoprotein nuclear expression, we demonstrated 99.9% specificity for detecting prostate tumor cells using a highly specific anti-ERG monoclonal antibody. The ERG oncoprotein expression correlated well with fusion transcript or gene fusion in randomly selected specimens. Strong concordance of ERG-positive foci of prostatic intraepithelial neoplasia (PIN) with ERG-positive carcinoma (82 out of 85 sections with PIN, 96.5%) affirms the biological role of ERG in clonal selection of prostate tumors in 65% (86 out of 132) of patients. Conversely, ERG negative PINs were associated with ERG-negative carcinoma. Taken together, the homogeneous and strong ERG expression detected in individual tumors establishes the potential for ERG oncoprotein-based stratification of CaP.
    Prostate cancer and prostatic diseases 09/2010; 13(3):228-37. · 2.10 Impact Factor

Publication Stats

5k Citations
531 Downloads
751.24 Total Impact Points

Institutions

  • 2013
    • Rajiv Gandhi Cancer Institute & Research Centre
      New Dilli, NCT, India
  • 1994–2013
    • Uniformed Services University of the Health Sciences
      • Department of Surgery
      Maryland, United States
  • 2012
    • Tulane University
      New Orleans, Louisiana, United States
  • 1984–2012
    • Walter Reed National Military Medical Center
      • Department of Surgery
      Washington, Washington, D.C., United States
  • 1987–2011
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 2008
    • The Queen's Medical Center
      Honolulu, Hawaii, United States
  • 2007
    • National Institutes of Health
      • Division of Cancer Prevention
      Bethesda, MD, United States
  • 2001–2006
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2005
    • Northwestern Memorial Hospital
      Chicago, Illinois, United States
  • 1999–2001
    • Georgetown University
      • Department of Radiology
      Washington, D. C., DC, United States
    • Shady Grove Adventist Hospital
      Maryland, United States
  • 1997–1999
    • University of Cologne
      • • Department of Urology
      • • Department of Neurology
      Köln, North Rhine-Westphalia, Germany
  • 1998
    • The Catholic University of America
      • Department of Electrical Engineering and Computer Science
      Washington, D. C., DC, United States
  • 1990
    • The Washington Hospital
      Washington, Pennsylvania, United States
  • 1989
    • Auburn University
      Auburn, Alabama, United States