ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells (original) (raw)
Related papers
Nature Medicine, 2013
Studies of ETS-mediated prostate oncogenesis have been hampered by the lack of suitable experimental systems. Here we describe a new conditional mouse model which gives robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG significantly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included restoration of AR transcriptional outut and genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETV1 positively regulated AR cistrome and transcriptional output in ETV1translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, ERG and ETV1 expression correlated with higher AR transcriptional output in PTEN-negative prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis
Nature, 2017
Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in ...
Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate
Nature Genetics, 2009
Chromosomal translocations involving the ERG locus are frequent events observed in human prostate cancer pathogenesis, however the biologic role of ERG aberrant expression is controversial. Here we demonstrate that the aberrant expression of ERG is a progression event in prostate tumorigenesis. We find that prostate cancer specimens containing the TMPRSS2:ERG genetic rearrangement are significantly enriched for loss of the tumor suppressor PTEN. In concordance with these findings, over-expression of ERG in the transgenic mouse prostate promotes a marked acceleration and progression of HGPIN to prostatic adenocarcinoma in a Pten heterozygous background. In vitro over-expression of ERG promotes cell migration, a property necessary for tumorigenesis, without affecting proliferation. ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration are found up-regulated in the presence of ERG over-expression. Thus, ERG plays a distinct role in prostate cancer progression and cooperates with PTEN haploinsufficiency to promote progression of HGPIN to invasive adenocarcinoma.
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.
Journal of Cancer, 2015
Background: Despite a growing number of studies evaluating cancer of prostate (CaP) specific gene alterations, oncogenic activation of the ETS Related Gene (ERG) by gene fusions remains the most validated cancer gene alteration in CaP. Prevalent gene fusions have been described between the ERG gene and promoter upstream sequences of androgen-inducible genes, predominantly TMPRSS2 (transmembrane protease serine 2). Despite the extensive evaluations of ERG genomic rearrangements, fusion transcripts and the ERG oncoprotein, the prognostic value of ERG remains to be better understood. Using gene expression dataset from matched prostate tumor and normal epithelial cells from an 80 GeneChip experiment examining 40 tumors and their matching normal pairs in 40 patients with known ERG status, we conducted a cancer signaling-focused functional analysis of prostatic carcinoma representing moderate and aggressive cancers stratified by ERG expression. Results: In the present study of matched pairs of laser capture microdissected normal epithelial cells and well-to-moderately differentiated tumor epithelial cells with known ERG gene expression status from 20 patients with localized prostate cancer, we have discovered novel ERG associated biochemical networks. Conclusions: Using causal network reconstruction methods, we have identified three major signaling pathways related to MAPK/PI3K cascade that may indeed contribute synergistically to the ERG dependent tumor development. Moreover, the key components of these pathways have potential as biomarkers and therapeutic target for ERG positive prostate tumors.
A causal role for ERG in neoplastic transformation of prostate epithelium
Proceedings of the National Academy of Sciences, 2008
A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium.
Emerging biological observations in prostate cancer
Expert Review of Anticancer Therapy, 2010
Emerging biological observations in prostate cancer provide the opportunity for the development of novel approaches to prevention, detection and treatment. Two observations selected for discussion in this review revolve around the mechanisms of action of signaling through the androgen receptor (AR) and the TMPRSS2:ERG chromosomal rearrangement, a fusion protein seen in nearly 50% of prostate cancers. Despite being called androgen-independent, these prostate cancers continue to depend on AR signaling despite low serum androgen levels. AR reactivation in recurrent tumors is hypothesized to occur through multiple mechanisms: AR amplification, AR mutation, active AR signaling (despite low levels of androgen), AR coactivators, ligand-independent AR activation, enhanced local production of androgens, alternative sources of androgen and upregulation in antiapoptotic genes in prostate cancer cells. A major breakthrough in prostate cancer was the identification of recurrent fusions between the androgen-regulated gene, TMPRSS2 and the vets erythroblastosis virus E26 oncogene homolog, ERG. This fusion has been identified as a common molecular event in prostate cancer, seen in approximately 50% of primary prostate cancer. It seems clear that this fusion gene plays an early role in prostate cancer development and/or progression, and ongoing work is being performed to elucidate the association between this fusion transcript and cancer aggressiveness.
The Significance of ERG and Androgen Receptor Expression in Adenocarcinoma Prostate
PubMed, 2019
Background Fusions of transmembrane protease, serine 2 (TMPRSS2) with erythroblast transformation specific transcription factors have been found in prostate cancer. The v-etserythroblastosis virus E26 oncogene homologue (ERG) is a proto-oncogene of the erythroblast transformation specific transcription factor family. TMPRSS2-ERG fusion is the most common molecular alteration present in about 50% of prostatic adenocarcinomas. Androgen receptor (AR) plays a key role in prostate development and is involved in the progression of prostate cancer. Objective To evaluate the significance of combined ERG and AR expression in cases of prostatic adenocarcinoma. Method The study was conducted at Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. Formalin fixed-paraffin embedded archival prostatic tissue specimens were obtained. A total of 10 cases of prostatic adenocarcinoma were included in the study. Immunohistochemistry for Androgen receptor was done by the standard protocol. Multiplex immunohistochemical staining was done for ERG+CK5 using a primary antibody cocktail of mouse and rabbit antibodies. Result Specific AR immunostaining was exclusively nuclear and was present in all 10 cases in varying intensity. Specific ERG immunostaining was nuclear and was present in seven cases (70%) and absent in three cases (30%). The three cases that were negative for ERG had a Gleason score of ≤ 6 and the AR staining was strong and present in about 90% of the cells. Gleason score was directly related to the ERG staining while AR staining was inversely related to the ERG staining. Conclusion The prognostic value of combined ERG and AR over-expression, its associated genes should be further investigated as potential therapeutic targets in prostate cancer progression. Preliminary data is being presented. Larger prospective studies with survival analysis are essential for prognostic significance.
Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications
Medicines, 2019
Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5 untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.