From Indolent to Metastatic

Science Signaling  15 Jan 2013:
Vol. 6, Issue 258, pp. ec13
DOI: 10.1126/scisignal.2003962

The growth and metastasis of prostate tumors arising from loss of the lipid and protein phosphatase PTEN is initially restrained by transforming growth factor–β (TGF-β) signaling, which activates the transcription factor SMAD4 to increase the expression of various genes, including those encoding the cell cycle regulators cyclin D1 and p21. Qin et al. investigated the mechanisms by which slowly growing, nonmetastatic (indolent) PTEN-null prostate tumors overcome the negative feedback provided by TGF-β signaling and become malignant. A greater proportion of human prostate tumors showed increased staining for the transcription factor COUP-TFII in the nucleus compared with normal prostate epithelial cells. Furthermore, increased abundance of COUP-TFII predicted the risk of recurrence in individuals with prostate cancer. Prostate tumor progression in mice with a prostate-specific deletion of Pten was delayed by a concomitant prostate-specific deletion of COUP-TFII and was enhanced by prostate-specific overexpression of COUP-TFII. Individuals with prostate cancer could be stratified into low- and high-risk groups for recurrence according to the abundance of transcripts for PTEN, SMAD4, p21, cyclin D1, and a COUP-TFII gene signature obtained from prostate cancer PC3 cells. In PC3 cells, knockdown of COUP-TFII increased TGF-β–induced gene transcription and the activity of a reporter gene for SMAD4. COUP-TFII coimmunoprecipitated with SMAD4 from human tumor samples, and the binding of SMAD4 to the promoters of the genes encoding p21 and cyclin D1 was decreased by COUP-TFII overexpression in mice with a prostate-specific deletion of Pten. These results suggested that COUP-TFII prevented the binding of SMAD4 to the promoters of its target genes. Thus, COUP-TFII neutralizes TGF-β signaling in PTEN-null prostate tumors to enable growth and metastasis.

J. Qin, S.-P. Wu, C. J. Creighton, F. Dai, X. Xie, C.-M. Cheng, A. Frolov, G. Ayala, X. Lin, X.-H. Feng, M. M. Ittmann, S.-J. Tsai, M.-J. Tsai, S. Y. Tsai, COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature 493, 236–240 (2013). [PubMed]