Estradiol-ERβ2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion

Hogyoung Kim; Amrita Datta; Sudha Talwar; Sarmad N. Saleem; Debasis Mondal; Asim B. Abdel-Mageed

doi:10.18632/oncotarget.11355

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Research Papers:

Estradiol-ERβ2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion

Hogyoung Kim, Amrita Datta, Sudha Talwar, Sarmad N. Saleem, Debasis Mondal and Asim B. Abdel-Mageed _

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Oncotarget. 2017; 8:62820-62833. https://doi.org/10.18632/oncotarget.11355

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Abstract

Hogyoung Kim1, Amrita Datta1, Sudha Talwar1, Sarmad N. Saleem1, Debasis Mondal2 and Asim B. Abdel-Mageed1,2,3

1Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA

2Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA

3Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA

Correspondence to:

Asim B. Abdel-Mageed, email: [email protected]

Keywords: estrogen, ERβ2, TMPRSS2:ETV5, IGF-1R, prostate cancer

Received: September 02, 2015 Accepted: July 26, 2016 Published: August 17, 2016

ABSTRACT

Estrogen receptor beta (ERβ) splice variants are implicated in prostate cancer (PC) progression; however their underlying mechanisms remain elusive. We report that non-canonical activation of estradiol (E₂)-ERβ2 signaling axis primes growth, colony-forming ability and migration of the androgen receptor (AR)-null castration-resistant PC (CRPC) cells under androgen-deprived conditions (ADC). The non-classical E₂-ERβ2 mediates phosphorylation and activation of Src-IGF-1R complex, which in turn triggers p65-dependent transcriptional upregulation of the androgen-regulated serine protease TMPRSS2:ETV5a/TMPRSS2:ETV5b gene fusions under ADC. siRNA silencing of TMPRSS2 and/or ETV5 suggests that TMPRSS2:ETV5 fusions facilitates the E₂-ERβ induced growth and migration effects via NF-κB-dependent induction of cyclin D1 and MMP2 and MMP9 in PC-3 cells. Collectively, our results unravel the functional significance of oncogenic TMPRSS2:ETV5 fusions in mediating growth and migration of E₂-ERβ2 signaling axis in CRPC cells. E₂-ERβ2 signaling axis may have significant therapeutic and prognostic implications in patients with CRPC.

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Research Papers:

Estradiol-ERβ2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion

Abstract