COUP-TFII promotes progression of PTEN-null prostate cancer by suppressing TGF-α signaling.

  • Major finding: COUP-TFII promotes progression of PTEN-null prostate cancer by suppressing TGF-β signaling.

  • Mechanism: COUP-TFII sequesters SMAD4 from TGF-β target gene promoters to overcome growth inhibition.

  • Impact: Inhibition of COUP-TFII, which correlates with tumor recurrence, may block disease progression.

Loss of the tumor suppressor PTEN frequently occurs in prostate cancer and drives the formation of low-grade prostatic intraepithelial neoplasia (PIN). However, the mechanisms that promote metastasis of these indolent precursor lesions are unknown. Qin and colleagues investigated whether nuclear receptor subfamily 2, group F, member 2 (NR2F2, also known as COUP-transcription factor II [COUP-TFII]), a transcription factor that is aberrantly expressed in many tumors, contributes to progression of PTEN-null prostate tumors. COUP-TFII expression was elevated in a panel of human prostate cancers and in metastatic tumors compared with normal prostate tissue and was predictive of increased risk of tumor recurrence and decreased survival, indicating that COUP-TFII may promote disease progression. In support of this idea, prostate-specific ablation of the Nr2f2 gene in Pten-null mice prevented progression of low-grade PIN lesions to advanced PIN or adenocarcinoma and diminished cancer cell proliferation without affecting angiogenesis. Conversely, although COUP-TFII alone was not sufficient to initiate tumorigenesis, its overexpression cooperated with Pten loss to accelerate the development of PIN and progression to invasive adenocarcinoma and enhanced metastasis to the lung and lymph nodes. COUP-TFII ablation in prostate cancer cells augmented TGF-β signaling, which serves as a growth barrier to tumor progression, and induced senescence. Additionally, COUP-TFII was inversely correlated with TGF-β signaling in human prostate tumors, suggesting that suppression of TGF-β-dependent gene expression by COUP-TFII facilitates metastasis. This inhibition of TGF-β required the interaction of COUP-TFII with SMAD4, which significantly diminished SMAD4 binding to TGF-β target gene promoters, and Smad4 deletion restored invasive tumor growth in mice lacking COUP-TFII. These results demonstrate that COUP-TFII-mediated inhibition of TGF-β is necessary for PTEN-null prostate cancer progression and suggest that blockade of this nuclear receptor may limit metastatic spread.

Qin J, Wu SP, Creighton CJ, Dai F, Xie X, Cheng CM, et al. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature Nov 28 2012 [Epub ahead of print].