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

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

Oncotarget. 2016 Aug 17;8(38):62820-62833. doi: 10.18632/oncotarget.11355. eCollection 2017 Sep 8.

Authors

Hogyoung Kim¹, Amrita Datta¹, Sudha Talwar¹, Sarmad N Saleem¹, Debasis Mondal², Asim B Abdel-Mageed^{1

2

3}

Affiliations

¹ Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.
² Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.
³ Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.

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.

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