Abnormal expression of the ERG transcription factor in prostate cancer cells activates osteopontin.

Osteopontin (OPN) is an extracellular matrix glycophosphoprotein that plays a key role in the metastasis of a wide variety of cancers. The high level of OPN expression in prostate cells is associated with malignancy and reduced survival of the patient. Recent studies on prostate cancer (PCa) tissue have revealed recurrent genomic rearrangements involving the fusion of the 5' untranslated region of a prostate-specific androgen-responsive gene with a gene coding for transcription factors from the ETS family. The most frequently identified fusion gene is TMPRSS2:ERG, which causes ERG protein overexpression in PCa cells. ERG is a transcription factor linked to skeletogenesis. This study was designed to test whether ERG and the product of the TMPRSS2:ERG fusion gene modulate OPN gene expression in PCa cells. To characterize ERG and TMPRSS2:ERG transcriptional activity of OPN, we focused on ETS binding sites (EBS) localized in conserved regions of the promoter. Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter. Moreover, stable transfection of prostate tumor cell lines by TMPRSS2:ERG upregulates endogenous OPN expression. Finally, in human prostate tumor samples, detection of the TMPRSS2:ERG fusion gene was significantly associated with OPN overexpression. Taken together, these data suggest that OPN is an ERG-target gene in PCa where the abnormal expression of the transcription factor ERG, due to the TMPRSS2:ERG fusion, disturbs the expression of genes that play an important role in PCa cells and associated metastases.

Flajollet S ，Tian TV ，Flourens A ，Tomavo N ，Villers A ，Bonnelye E ，Aubert S ，Leroy X ，Duterque-Coquillaud M ... -  《-》

TMPRSS2/ERG fusion gene expression alters chemo- and radio-responsiveness in cell culture models of androgen independent prostate cancer.

The androgen regulated transmembrane serine protease (TMPRSS2) and ETS transcription factor (ERG) gene fusion is a strong prognostic factor for disease recurrence following prostatectomy. Expression of TMPRSS2/ETS-related gene (ERG) fusion gene transcripts is linked with tumor proliferation, invasion, and an aggressive phenotype. The aim of this study was to define the effect of TMPRSS2/ERG fusion gene expression on chemo- and radiosensitivity in prostate tumor cell lines. Clonogenic survival of PC3 and DU145 cells stably expressing TMPRSS2/ERG Types III and VI fusion genes was measured after X-irradiation (0-8 Gy) and Paclitaxel. Cell cycle changes and DNA double-strand break induction and repair were assessed. Differential gene expression was measured by microarray analysis. ERG signaling pathway interactions were studied using Ariadne Pathway Studio. Expression of the TMPRSS2/ERG fusions in PC3 cells increased radiation sensitivity and decreased paclitaxel sensitivity. Increased radiosensitivity was associated with persistent DNA breaks 24 hr post-irradiation, down-regulation of genes involved in DNA repair and mitosis and up-regulation of ETV, an ETS transcription factor. However, DU145 Types III and VI demonstrated a different sensitivity phenotype and gene expression changes. Pathway analysis of ERG signaling further illustrated the variation between the PC3 and DU145 cell lines containing TMPRSS2/ERG fusions. The effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio- and chemosensitivity in vivo.

Swanson TA ，Krueger SA ，Galoforo S ，Thibodeau BJ ，Martinez AA ，Wilson GD ，Marples B ... -  《-》

TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer.

Hermans KG ，van Marion R ，van Dekken H ，Jenster G ，van Weerden WM ，Trapman J ... -  《CANCER RESEARCH》

Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer.

Laxman B ，Tomlins SA ，Mehra R ，Morris DS ，Wang L ，Helgeson BE ，Shah RB ，Rubin MA ，Wei JT ，Chinnaiyan AM ... -  《NEOPLASIA》

Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2.

Tian TV ，Tomavo N ，Huot L ，Flourens A ，Bonnelye E ，Flajollet S ，Hot D ，Leroy X ，de Launoit Y ，Duterque-Coquillaud M ... -  《-》