COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis

Qin et al. Nature 493: 236-240, 2013

Speaker: Chung-Tend Wang (王崇騰)                           Time: 14:00~15:00, May 29, 2013

Commentator: Dr. Cheng-Chan Lu (呂政展老師)          Place: Room 601

Abstract:

Loss of phosphatase and tensin homologue (PTEN) function, through deletion, mutation, or reduced expression, has been well documented in prostate cancer with an estimated frequency of ∼40%.¹ However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor(TGF-β) signalling triggered by PTEN loss will form a growth barrier to inhibit prostate tumorigenesis.² Expression analysis of the microarray database Oncominerevealed higher COUP-transcription factor II (COUP-TFII) expression in prostate tumour cells and in metastatic prostate cancer than in primary prostate cancer.³ In this study, the authors found that high levels of COUP-TFII correlated with increased risk of tumor recurrence and decreased survival. In support of this idea, they further showed that prostate-specific knockout of the COUP-TFII gene in PTEN-null mice prevented progression of low-grade prostatic intraepithelial neoplasia (PIN) lesions to advanced PIN or adenocarcinoma and diminished cancer cell proliferation without affecting angiogenesis. By contrast, COUP-TFII overexpression cooperated with PTEN loss accelerated the development of PIN and progression to invasive disease and enhanced metastasis. COUP-TFII was inversely correlated with TGF-β signaling in human prostate tumors, suggesting that COUP-TFII facilitates metastasis by suppressing TGF-β-dependent gene expression. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and support COUPTFII as a potential drug target for the intervention of metastatic human prostate cancer.

References

1.      Pourmand, G. et al. (2007) Role of PTEN gene in progression of prostate cancer Urol. J. 4: 95–100.

2.      Ding, Z. et al. (2011) SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470: 269–273.

3.      Tomlins, S. A. et al. (2007) Integrative molecular concept modeling of prostate cancer progression. Nat. Genet. 39: 41–51.