Overexpression of Ets-1 proto-oncogene in latent and clinical prostatic carcinomas (original) (raw)
Related papers
ETS transcription factors and prostate cancer: The role of the family prototype ETS-1 (Review)
International Journal of Oncology, 2012
The ETS family of transcription factors is known to play important roles in various biological processes such as development, differentiation, proliferation, apoptosis, migration, tissue remodeling, invasion and angiogenesis in various cell types including B cells, endothelial cells, fibroblasts as well as diverse neoplastic cells. In prostate cancer, recurrent gene fusions involving members of the ETS family are frequently reported. ETS-1, the prototype of the ETS family, is expressed in different cell types and is known to play various roles during both physiological and pathological conditions. In this review, we focus on studies investigating the role of ETS-1 in prostate cancer. Contents 1. Introduction 2. ETS gene fusions in prostate cancer 3. Expression of the ETS family in prostate cancer 4. The roles of the ETS-family prototype ETS-1 in prostate cancer 5. ETS-1, a potential regulator of the ETS-family in prostate cancer 6. Conclusion
Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome
Oncogene, 2005
Transcription factors encoded by the ETS family of genes are central in integrating signals that regulate cell growth and differentiation, stress responses, and tumorigenesis. This study, analysing laser microdissected paired benign and malignant prostate epithelial cells from prostate cancer (CaP) patients (n ¼ 114; 228 specimen) by GeneChip and quantitative real-time RT-PCR, identifies ETS-related gene (ERG), a member of the ETS transcription factor family, as the most frequently overexpressed proto-oncogene in the transcriptome of malignant prostate epithelial cells. Combined quantitative expression analysis of ERG with two other genes commonly overexpressed in CaP, AMACR and DD3, revealed overexpression of at least one of these three genes in virtually all CaP specimen (54 of 55). Comprehensive evaluation of quantitative ERG1 expression with clinicopathological features also suggested that ERG1 expression level in prostate tumor cells relative to benign epithelial cells is indicator of disease-free survival after radical prostatectomy.
International journal of molecular medicine, 2011
The ETS family of transcription factors plays important roles in both normal and neoplastic cells for different biological processes such as proliferation, differentiation, development, transformation, apoptosis, migration, invasion and angiogenesis. The 27 ETS factors are probably a part of complex regulatory networks including interactions among family members. In human prostate cancer, rearrangements have been found in several genes of the ETS family resulting in chimeric oncoproteins. In a previous study we found that the ETS family prototype, Ets-1 affects biological properties of PC3 prostate cancer cells. In a first effort to understand the cooperative interactions between different ETS factors in prostate cancer, in the present study we examined the expression pattern of all 27 ETS members using quantitative RT-PCR (qRT-PCR) in the androgen-sensitive VCaP and LNCaP, and the androgen-insensitive PC3 and DU-145 prostate cancer cell lines as well as in human prostate cancer tis...
International journal of molecular medicine, 2011
Ets-1 is the prototype of the ETS family of transcription factors and is suggested to play an important role in the malignant progression of prostatic carcinomas. Therefore, in this study we investigated the effect of blocking Ets-1 in PC3 prostate cancer cells on genes involved in the metastatic cascade, and correlated these findings with prostate cancer tissues. Two stable PC3 cell cultures were established by transfection with either an Ets-1 inverse antisense expression vector or a mock control vector. The effect of blocking Ets-1 on genes involved in the metastatic cascade was assessed by a comprehensive gene expression microarray analysis of Ets-1 inverse and mock control cells. Correlating the sets of genes found in the PC3 microarray data with prostate cancer tissues was performed by verifying the genes in a comprehensive gene expression microarray analysis of RNA extracted from laser microdissected normal prostate glands and from carcinoma glands taken from prostate cancer ...
Proceedings of the National Academy of Sciences, 2009
Chromosomal rearrangements involving erythroblast transformation specific (ETS) family transcription factors were recently defined as the most common genetic alterations in human prostate cancer. Despite their prevalence, it is unclear what quantitative role they play in either initiation or progression of the disease. Using a lentiviral transduction and dissociated cell prostate regeneration approach, we find that acutely increased expression of ETS proteins in adult murine prostate epithelial cells is sufficient to induce the formation of epithelial hyperplasia and focal prostatic intraepithelial neoplasia (PIN) lesions, but not progression to carcinoma. However, combined expression of ERG with additional genetic alternations associated with human prostate cancer can lead to aggressive disease. Although ERG overexpression does not cooperate with loss of the tumor suppressor p53, it does collaborate with alterations in PI3K signaling, such as Pten knockdown or AKT up-regulation, to produce a well-differentiated adenocarcinoma. Most striking is our finding that overexpression of androgen receptor (AR) does not give rise to any hyperplastic lesions, but when combined with high levels of ERG, it promotes the development of a more poorly differentiated, invasive adenocarcinoma. These findings suggest that in human prostate cancer, the most potent function of ETS gene fusions may be to synergize with alternative genetic events and provide different pathways for carcinoma production and invasive behavior. Our results provide direct evidence for selective cooperating events in ERG-induced prostate tumorigenesis and offer a rational basis for combined therapeutic interventions against multiple oncogenic pathways in prostate cancer.
2012
The ETS family of transcription factors is known to play important roles in various biological processes such as development, differentiation, proliferation, apoptosis, migration, tissue remodeling, invasion and angiogenesis in various cell types including B cells, endothelial cells, fibroblasts as well as diverse neoplastic cells. In prostate cancer, recurrent gene fusions involving members of the ETS family are frequently reported. ETS-1, the prototype of the ETS family, is expressed in different cell types and is known to play various roles during both physiological and pathological conditions. In this review, we focus on studies investigating the role of ETS-1 in prostate cancer.
Cancer Research, 2009
ETS variant 1 (ETV1), also known as ETS-related protein 81, is overexpressed in prostate tumors, but whether and how this transcription factor affects tumorigenesis has remained elusive. Here, we show that ETV1 is primarily overexpressed in the most aggressive human prostate tumors. Transgenic ETV1 mice developed prostatic intraepithelial neoplasia as well as hyperplasia/neoplasia in seminal vesicles. Moreover, ETV1 cooperated with the androgen receptor (AR) to bind to the prostate-specific antigen enhancer and stimulate gene transcription. Consistent with its ability to physically interact with AR, ETV1 rendered an ETV1 binding site-driven reporter androgen inducible, and, on the other hand, ETV1 superinduced transcription from an AR binding site on androgen stimulation. In conclusion, our study substantiates that ETV1 overexpression is an underlying cause in the development of prostate and possibly also seminal vesicle cancer. Its interaction with and activation of AR provides a molecular mechanism on how ETV1 exerts its deleterious function. Thus, inhibiting ETV1 or blocking its interaction with AR may represent novel strategies in prostate cancer therapy. [Cancer Res 2009;69(20):8102-10]
ETS rearrangements and prostate cancer initiation
Nature, 2009
The first recurrent translocation event in prostate cancer has been recently described. It results in the translocation of an ETS transcription factor (ERG or ETV1) to the TMPRSS2 promoter region, which contains androgen responsive elements. The TMPRSS:ERG genetic rearrangement has been reported to occur in approximately 40% of primary prostate tumors (ETV1 genetic rearrangements occurring at a much lower frequency) and results in an aberrant androgen regulated expression of ERG. 1,2,3 While Tomlins et al. 4 concluded that ETS genetic rearrangements are sufficient to initiate prostate neoplasia, we argue that ETS genetic rearrangements may in fact, represent progression events rather than initiation events in prostate tumorigenesis. To this end, we demonstrate that the prostate specific over-expression of ERG does not initiate prostate tumorigenesis.
Applied Immunohistochemistry & Molecular Morphology, 2012
ETS-1 protooncogene is an important transcription factor that plays a role in the regulation of physiological processes, such as cell proliferation and differentiation. ETS-1 is thought to be related to the growth of carcinoma cells by its regulation of the transcription of matrix metalloproteinases and urokinase-type plasminogen activator. In this study, we aimed to investigate the expression pattern of ETS-1 oncoprotein in urothelial carcinomas of the urinary bladder and determine its relationship with histopathologic parameters, including tumor grade and stage. One hundred six specimens of urothelial carcinoma and a total of 14 normal urothelium were analyzed immunohistochemically with anti-ETS-1 monoclonal antibody. The normal urothelium showed positive ETS-1 immunostaining. ETS-1 expression remained high in low-grade and noninvasive tumors, whereas it frequently decreased in high-grade or invasive carcinomas. Interestingly, ETS-1 was highly expressed in the basal cell layer of the noninvasive urothelial carcinomas. ETS-1 expression showed a strong negative correlation with the tumor grade (P<0.001; r, À 0.67) and stage (P<0.001; r, À 0.75). The nonmuscle-invasive tumors (pTa+pT1) and noninvasive tumors (pTa) had significantly higher ETS-1 expression than the muscle-invasive tumors (pT2; P<0.001) and invasive tumors (pT1+pT2; P<0.001), respectevely. Results of our study show that decreased ETS-1 expression is significantly associated with high grade and advanced stage in urothelial carcinomas of the urinary bladder, and that the downregulation of ETS-1 expression may be a marker of the aggressiveness of such malignancies.
Oncology Reports, 2004
We previously reported that prostate derived Ets transcription factor (PDEF) is a breast tumor-associated molecule. To obtain further insights into PDEF expression in other human tumor types, a cDNA library database from human adult normal and tumor tissues was compiled and searched for PDEF distribution. The results showed that PDEF is present at relative higher frequencies in the cDNA libraries from brain, breast, lung and ovarian tumors in comparison to those from the corresponding normal tissues. RT/PCR analysis of PDEF expression in ovarian tumors confirmed that PDEF is expressed in 36 out of 51 (71%) ovarian tumors. Further comparison of the distribution of PDEF with other widely recognized cancer-associated molecules showed that PDEF has more restricted distributions than Her-2/neu, Bcl-2, survivin or telomerase in cDNA libraries from normal human tissues and more increased distribution than Her-2/neu, CA-125, Bcl-2, survivin and telomerase in cDNA libraries from brain (except survivin), breast, lung and ovarian tumors. These data together show a better tumor-association for PDEF and suggest that PDEF is a more suitable target for developing specific cancer therapies.