Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer

Setlur, Sunita R.; Mertz, Kirsten D.; Hoshida, Yujin; Demichelis, Francesca; Lupien, Mathieu; Perner, Sven; Sboner, Andrea; Pawitan, Yudi; Andrén, Ove; Johnson, Laura A.; Tang, Jeff K. T.; Adami, Hans Olov; Calza, Stefano; Chinnaiyan, Arul M.; Rhodes, Daniel R.; Tomlins, Scott A.; Fall, Katja; Mucci, Lorelei A.; Kantoff, Philip W.; Stampfer, Meir J.; Andersson, Sven‐Olof; Varenhorst, Eberhard; Johansson, Jan; Brown, Myles; Golub, Todd R.; Rubin, Mark A.

doi:10.1093/jnci/djn150

Cited by 295 publications

(289 citation statements)

References 26 publications

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“…In two Swedish watchful waiting cohorts, the incidence was 15% (17/111) and 18% (62/354), respectively. 9,10 In these studies, the prostate cancer samples were obtained by transurethral resection of the prostate (TURP), representing mainly transition zone carcinomas. The included patients were restricted to those at early clinical stages (T1a-b, Nx, M0).…”

Section: Discussionmentioning

confidence: 99%

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

Miyagi

Sasaki

Fujinami³

et al. 2010

Modern Pathology

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The incidence and clinical significance of the TMPRSS2:ERG gene fusion in prostate cancer has been investigated with contradictory results. It is now common knowledge that significant variability in gene alterations exists according to ethnic background in various kinds of cancer. In this study, we evaluated gene fusions involving the ETS gene family in Japanese prostate cancer. Total RNA from 194 formalin-fixed and paraffin-embedded prostate cancer samples obtained by radical prostatectomy was subjected to reversetranscriptase polymerase chain reaction to detect the common TMPRSS2:ERG T1-E4 and T1-E5 fusion transcripts and five other non-TMPRSS2:ERG fusion transcripts. We identified 54 TMPRSS2:ERG-positive cases (54/194, 28%) and two HNRPA2B1:ETV1-positive cases (2/194, 1%). The SLC45A3-ELK4 transcript, a fusion transcript without structural gene rearrangement, was detectable in five cases (5/194, 3%). The frequencies of both TMPRSS2:ERG-and non-TMPRSS2:ERG-positive cases were lower than those reported for European, North American or Brazilian patients. Internodular heterogeneity of TMPRSS2:ERG was observed in 5 out of 11 multifocal cases (45%); a frequency similar to that found in European and North American cases. We found a positive correlation between the TMPRSS2:ERG fusion and a Gleason score of r7 and patient age, but found no relationship with pT stage or plasma prostate-specific antigen concentration. To exclude the possibility that Japanese prostate cancer displays novel TMPRSS2:ERG transcript variants or has unique 5 0 fusion partners for the ETS genes, we performed 5 0 RACE using fresh-frozen prostate cancer samples. We identified only the normal 5 0 cDNA ends for ERG, ETV1 and ETV5 in fusion-negative cases. Because we identified a relatively low frequency of TMPRSS2:ERG and other fusions, further evaluation is required before this promising molecular marker should be introduced into the management of Japanese prostate cancer patients.

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Section: Discussionmentioning

confidence: 99%

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

Miyagi

Sasaki

Fujinami³

et al. 2010

Modern Pathology

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“…Another line of evidence supporting the role of SEPT9 in oncogenesis is derived from prostate cancer tumors with the chromosomal fusion between the transmembrane protease Ser 2 (TMPRSS2) and ERG, a member of the erythroblast transformation-specific transcription factor family (15). These tumors express significantly higher SEPT9 levels compared with tumors without the translocation and are associated with a more aggressive clinical course (16).…”

Section: Introductionmentioning

confidence: 99%

Targeted Knockdown of SEPT9_v1 Inhibits Tumor Growth and Angiogenesis of Human Prostate Cancer Cells Concomitant with Disruption of Hypoxia-Inducible Factor-1 Pathway

Sharon

Golan

Mabjeesh

2010

Molecular Cancer Research

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Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the hypoxic response pathway. We recently identified a novel interaction between HIF-1α and the mammalian septin family member, septin 9 protein, isoform 1 (SEPT9_i1), a protein product of septin 9 transcript variant 1 (SEPT9_v1). Septins are a highly conserved family of GTP-binding cytoskeletal proteins that are implicated in multiple cellular functions, including oncogenesis. SEPT9_i1 binds and stabilizes HIF-1α protein and stimulates HIF-1 transcriptional activity by preventing its RACK1-mediated ubiquitination and degradation. SEPT9_i1-HIF-1 activation promotes tumor growth and angiogenesis. The effect of SEPT9_v1 silencing in prostate cancer cells was studied. SEPT9_v1 stable knockdown was generated in PC-3 cells using a specific shRNA. SEPT9_v1 silencing reduced HIF-1α protein expression and inhibited HIF-1 transcriptional activity. SEPT9_v1 knockdown affected cell morphology, deregulated cell cycle, and decreased migration. The antiproliferative effect of shSEPT9_v1 was abolished in HIF-1α knockout colon cancer cells. In vivo, SEPT9_i1 depletion reduced HIF-1α protein expression, cellular proliferation, tumor growth, and angiogenesis. These results provide new insights and validation for applying SEPT9_v1 as a potential target for antitumor therapy by interrupting the HIF-1 pathway. Mol Cancer Res; 8(5); 643-52. ©2010 AACR.

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“…35 In two population-based studies from Sweden and the United Kingdom, 15%-20% of men diagnosed with incidental prostate cancer had tumors that harbored TMPRSS2:ERG. 27,40,41 It is worth highlighting that the 354 incidental cancers from the Swedish cohorts were detected in five population-based cohorts prior to PSA screening. 40 All of the tumors were detected on transurethral resection of the prostate samples, which differs from the prostatectomy series.…”

Section: A Multitude Of Gene Fusions In Prostate Cancermentioning

confidence: 99%

“…27,40,41 It is worth highlighting that the 354 incidental cancers from the Swedish cohorts were detected in five population-based cohorts prior to PSA screening. 40 All of the tumors were detected on transurethral resection of the prostate samples, which differs from the prostatectomy series. Although some have suggested that there may be a genetic component to this lower frequency in the Swedish population, we have determined that, in a PSA-screened biopsy cohort from Ö rebro, the percentage is approximately 45%, which is similar to all other PSA-screened hospital-based cohorts (Svensson and Rubin, unpublished.…”

Section: A Multitude Of Gene Fusions In Prostate Cancermentioning

confidence: 99%

ETS rearrangements in prostate cancer

Rubin¹

2012

Asian J Androl

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Prostate cancer is a clinically and molecularly heterogeneous disease. Understanding the biologic underpinning of prostate cancer is necessary to best determine how biology is associated with the risk of disease progression and how this understanding might provide insight into the development of novel therapeutic approaches. The focus of this review is on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a basic understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease.

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Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer

Abstract: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.

Cited by 295 publications

References 26 publications

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

Targeted Knockdown of SEPT9_v1 Inhibits Tumor Growth and Angiogenesis of Human Prostate Cancer Cells Concomitant with Disruption of Hypoxia-Inducible Factor-1 Pathway

ETS rearrangements in prostate cancer

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