ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients

Baena, Esther; Shao, Zongshu; Linn, Douglas E.; Glass, Kimberly; Hamblen, Melanie; Fujiwara, Yuko; Kim, Jonghwan; Nguyen, Minh; Zhang, Xin; Godinho, Frank J.; Bronson, Roderick T.; Mucci, Lorelei A.; Loda, Massimo; Yuan, Guo Cheng; Orkin, Stuart H.; Li, Zhe

doi:10.1101/gad.211011.112

Cited by 173 publications

(223 citation statements)

References 70 publications

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“…Thus, we propose that there may be a cascade of ETS gene function in prostate cancer progression, in which the lateracting genes, such as ETV4, may be activated not by gene recombination but in response to signaling events. Interestingly, both ERG and ETV1 have been shown to influence the transcriptional program of the androgen receptor (19,23), which raises the important question of how ETV4 may interplay with androgen receptor signaling in advanced prostate cancer. Finally, our current findings shed light on the relationship between oncogenic ETS genes and Ras signaling.…”

Section: Discussionmentioning

confidence: 99%

“…The TMPRSS2-ERG fusion is highly prevalent in prostate cancer and is associated with disease outcome in some cases (13,15), and functionally cooperates with dysregulation of other key genes, including the PTEN tumor suppressor, in prostate cancer progression (16)(17)(18)(19). Notably, other oncogenic ETS genes (20), including ETV1, undergo translocation in prostate cancer and collaborate with PTEN in cancer progression (21)(22)(23), and at least one tumor-suppressive ETS family member, ETS2, is mutated in advanced prostate cancer (8). Despite these findings, the complexity of ETS gene function during prostate cancer progression has not been fully resolved.…”

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confidence: 99%

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ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Aytés

Mitrofanova

Kinkade³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

129

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Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. M etastasis is a highly inefficient process that involves multiple steps, including invasion of local stroma, intravasation into the bloodstream and/or lymphatic system, and extravasation into a secondary tissue, which is thought to arise as a consequence of multiple molecular/epigenetic alterations in tumor cells, as well as in the microenvironment of metastatic sites (1-4). Nonetheless, despite its inefficiency, most cancer deaths are due to metastases and our current inability to treat them once they arise. In particular, in prostate cancer, the locally invasive disease has a nearly 100% survival rate, whereas metastatic prostate cancer is very often lethal (5).Recent analyses have identified key molecular pathways that are frequently dysregulated during prostate cancer progression, as a consequence of copy number alterations, chromosomal rearrangements, and other aberrant genetic/epigenetic events (6-10). For example, loss of chromosomal region 8p21 and coincident haploinsufficiency for the NKX3.1 homeobox gene occurs frequently in precursor lesions known as prostatic intraepithelial neoplasia (PIN) and are associated with prostate cancer initiation (11,12). Another early event in prostate tumorigenesis is the formation of the TMPRSS2-ERG rearrangement, which fuses the transmembrane protease TMPRSS2 promoter with the coding region of the ETS transcription factor ERG (13, 14). The TMPRSS2-ERG fusion is highly prevalent in prostate cancer and is associated with disease out...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Aytés

Mitrofanova

Kinkade³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

129

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show abstract

“…However, in other studies, TMPRSS2-ERG GEMs did not even develop PIN. Among the progeny from crossbreeding Erg mice with Pten-knockout mice, PIN and micro-invasive cancer were observed , King et al 2009, Baena et al 2013, Chen et al 2013. Witte and colleagues provided additional evidence that ERG can cooperate with several different oncogenes or tumor suppressor genes in the development of mouse prostate tumors (Zong et al 2009).…”

Section: Biological and Molecular Functions Of Ets Proteins In Prostamentioning

confidence: 99%

“…ERG and ETV1 at least partially interact with overlapping binding sites, but might have different effects on target gene expression. ERG negatively regulates AR-regulated gene expression and ETV1 has the opposite effect (Baena et al 2013). As an example, although ERG inhibits PSA expression, ETVI seems to stimulate PSA expression (Shin et al 2009, Yu et al 2010.…”

Section: Biological and Molecular Functions Of Ets Proteins In Prostamentioning

confidence: 99%

ETS fusion genes in prostate cancer

Tandefelt¹,

Boormans²,

Hermans³

et al. 2014

Endocrine-Related Cancer

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Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostatespecific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2-ERG and other ETS gene fusions in prostate cancer.

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“…It has been defined as an oncoprotein overexpressed in breast cancer (6,7), prostatic carcinoma (8,9), melanoma (10), Ewing sarcoma (11) as well as GISTs, and plays a key role in neoplastic formation, development and progression. ChiP (12) confirmed the observation that ETV1 is a lineage-specific survival factor which cooperates with KIT in GISTs.…”

Section: Introductionmentioning

confidence: 99%

Altered expression of ETV1 and its contribution to tumorigenic phenotypes in gastrointestinal stromal tumors

Zhang¹,

Gu²,

Zhou³

et al. 2014

Oncology Reports

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Abstract. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. ETV1 is a unique transcription factor specific to GIST that has been reported to date. The present study aimed to determine aberrant ETV1 expression and its contribution to tumorigenesis in GISTs. Altered expression levels of ETV1 and its relevant signaling pathways were assessed using western blotting and quantitative real-time PCR in 72 paired patient tissue samples. In addition, immunochemistry was performed on 156 GISTs using tissue microarray to analyze the correlation between ETV1 and clinical parameters. The results revealed that ETV1 was highly expressed in the GISTs at both the transcription and protein levels. Immunochemical analysis revealed that increased expression of ETV1 was correlated with KIT in the 156 patients. In addition, the frequency of ETV1 positivity was higher when compared with KIT [50.0% (9/18) vs 38.9% (7/18)] particularly in high-risk GISTs. Analysis of western blotting data showed that total protein isoforms of Raf, MEK and ERK were similar in the GIST tissues as well as in the uninvolved normal tissues. In contrast, the level of phosphoRaf, phospho-MEK and phospho-ERK were decreased in the tumor group. Moreover, enhanced signaling molecules such as Bcl-2 and Dvl2/GSK-3β/β-catenin/Smad2 were detected, showing a significant difference in comparison with the uninvolved normal cases. We conclude that ETV1, a member of the ETS family, is upregulated in GISTs, and its signaling is integrated into a cellular signaling network for resistance to apoptosis, tumor cell invasion and survival.

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ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients

Cited by 173 publications

References 70 publications

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

ETS fusion genes in prostate cancer

Altered expression of ETV1 and its contribution to tumorigenic phenotypes in gastrointestinal stromal tumors

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