Upregulation of SPDEF is associated with poor prognosis in prostate cancer

SAM pointed domain-containing Ets transcription factor (SPDEF), a member of the ETS transcription factor family, has been associated with prostate cancer development; however, its role in tumour development and progression is controversial. In the present study, SPDEF expression was analysed on a tissue microarray with >12,000 prostate cancer samples. SPDEF expression levels were higher in most prostate cancer samples than in normal prostate epithelium, suggesting SPDEF was upregulated in cancer. Nuclear SPDEF expression was identified in 80% of prostate cancer samples, and considered weak in 26.4%, moderate in 40.1% and strong in 13.5% of cases. SPDEF positivity was significantly associated with tumour stage, Gleason grade, lymph node metastasis and PSA recurrence (all P<0.0001). SPDEF overexpression was more common in ERG positive (94%) than in ERG negative cancer (69%; P<0.0001). Elevated SPDEF expression predicted poor prognosis independent from established prognostic parameters, including Gleason grade, pT, pN, serum PSA level and nodal status (P<0.01). In summary, SPDEF overexpression was associated with aggressive behaviour, particularly in ERG negative prostate cancer, and may have potential for clinical application.

[1]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[2]  J. Mariadason,et al.  ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer , 2018, Molecules.

[3]  G. Sauter,et al.  13q deletion is linked to an adverse phenotype and poor prognosis in prostate cancer , 2018, Genes, chromosomes & cancer.

[4]  K. Li,et al.  Clinical significance of PSMA, TERT and PDEF in malignant tumors of the prostate. , 2017, European review for medical and pharmacological sciences.

[5]  Joseph Geradts,et al.  Prostate-derived Ets factor, an oncogenic driver in breast cancer , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[6]  K. Tsui,et al.  Prostate-derived ets factor represses tumorigenesis and modulates epithelial-to-mesenchymal transition in bladder carcinoma cells. , 2016, Cancer letters.

[7]  A. Haese*,et al.  Clinical Utility of Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens. , 2016, European urology.

[8]  G. Sauter,et al.  Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer , 2015, International journal of cancer.

[9]  G. Sauter,et al.  Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer , 2015, Clinical Cancer Research.

[10]  M. Medvedovic,et al.  SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene , 2014, PLoS genetics.

[11]  G. Sauter,et al.  Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer , 2014, Modern Pathology.

[12]  G. Sauter,et al.  SPINK1 expression is tightly linked to 6q15‐ and 5q21‐deleted ERG‐fusion negative prostate cancers but unrelated to PSA recurrence , 2013, The Prostate.

[13]  S. Kurtz,et al.  Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion‐positive prostate cancers , 2013, The Journal of pathology.

[14]  J. Korbel,et al.  Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions , 2013, Modern Pathology.

[15]  G. Sauter,et al.  CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. , 2013, Cancer research.

[16]  T. Khoury,et al.  Prostate derived Ets transcription factor and Carcinoembryonic antigen related cell adhesion molecule 6 constitute a highly active oncogenic axis in breast cancer , 2013, Oncotarget.

[17]  D. Berney,et al.  Standardization of Gleason grading among 337 European pathologists , 2013, Histopathology.

[18]  C. Plass,et al.  Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. , 2012, The American journal of pathology.

[19]  Timothy J Wilt,et al.  Radical prostatectomy versus observation for localized prostate cancer. , 2012, The New England journal of medicine.

[20]  I. Thompson,et al.  Prostate cancer--uncertainty and a way forward. , 2012, The New England journal of medicine.

[21]  Joshua J. Steffan,et al.  The Transcription Factor SPDEF Suppresses Prostate Tumor Metastasis* , 2012, The Journal of Biological Chemistry.

[22]  Bruce J Trock,et al.  Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. , 2012, European urology.

[23]  David P Turner,et al.  Mechanisms and functional consequences of PDEF protein expression loss during prostate cancer progression , 2011, The Prostate.

[24]  G. Wilding,et al.  Prostate‐derived Ets transcription factor (PDEF) is a potential prognostic marker in patients with prostate cancer , 2011, The Prostate.

[25]  A. Haese*,et al.  High level PSMA expression is associated with early psa recurrence in surgically treated prostate cancer , 2011, The Prostate.

[26]  M. Bhasin,et al.  Requirement of the Epithelium-specific Ets Transcription Factor Spdef for Mucous Gland Cell Function in the Gastric Antrum* , 2010, The Journal of Biological Chemistry.

[27]  R. Meacham,et al.  Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: Regulation of MMP 9 by PDEF , 2010, Molecular Cancer.

[28]  Hartwig Huland,et al.  Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer , 2010, Clinical Cancer Research.

[29]  David P Turner,et al.  PDEF is a negative regulator of colon cancer cell growth and migration , 2009, Journal of cellular biochemistry.

[30]  C. Cooper,et al.  ETS gene fusions in prostate cancer , 2009, Nature Reviews Urology.

[31]  M. Rubin,et al.  ETS gene fusions in prostate cancer: from discovery to daily clinical practice. , 2009, European urology.

[32]  K. Odunsi,et al.  Prostate‐derived Ets transcription factor as a favorable prognostic marker in ovarian cancer patients , 2008, International journal of cancer.

[33]  J. Geradts,et al.  Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression. , 2007, Human pathology.

[34]  M. Bhasin,et al.  Reduced PDEF expression increases invasion and expression of mesenchymal genes in prostate cancer cells. , 2007, Cancer research.

[35]  P. Mhawech-Fauceglia,et al.  Prostate-derived Ets Factor Is Overexpressed in Serous Epithelial Ovarian Tumors , 2007, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[36]  G. Daley,et al.  Novel role for PDEF in epithelial cell migration and invasion. , 2005, Cancer research.

[37]  W. Greco,et al.  Prostate derived Ets transcription factor shows better tumor-association than other cancer-associated molecules. , 2004, Oncology reports.

[38]  V. Sementchenko,et al.  Pdef expression in human breast cancer is correlated with invasive potential and altered gene expression. , 2003, Cancer research.

[39]  A. Sharrocks The ETS-domain transcription factor family , 2001, Nature Reviews Molecular Cell Biology.

[40]  A. Sood,et al.  Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[41]  T. Libermann,et al.  PDEF, a Novel Prostate Epithelium-specific Ets Transcription Factor, Interacts with the Androgen Receptor and Activates Prostate-specific Antigen Gene Expression* , 2000, The Journal of Biological Chemistry.

[42]  E. Fearon,et al.  Cancer progression , 1999, Current Biology.

[43]  J. Kononen,et al.  Tissue microarrays for high-throughput molecular profiling of tumor specimens , 1998, Nature Medicine.

[44]  This work is licensed under a Creative Commons Attribution-NonCommercial- NoDerivs 3.0 Licence. To view a copy of the licence please see: http://creativecommons.0rg/licenses/by-nc-nd/3.0/ INEQIMTES IN THE DELIVERY OF SERVICES TO A FEMALE FARM CLIENTELE: SOME~~ , 2010 .

[45]  A. Chinnaiyan,et al.  Recurrent gene fusions in prostate cancer , 2008, Nature Reviews Cancer.

[46]  M. Graefen,et al.  Tumour grade, proliferation, apoptosis, microvessel density, p53, and bcl-2 in prostate cancers: differences between tumours located in the transition zone and in the peripheral zone. , 2002, European urology.