Prostate cancer is a heterogeneous disease; in many men, particularly those diagnosed in old age, the disease can remain indolent for years or even decades, sometimes requiring no treatment other than careful monitoring.

In other cases, the tumour rapidly becomes aggressive and metastatic, and the five-year survival rate for men diagnosed with metastatic or Stage 4 prostate cancer is only about 30%.

It is therefore important to be able to distinguish tumours that are likely to become metastatic at as early a stage as possible, so that all patients can be offered the most appropriate treatment and those with indolent disease spared unpleasant treatment regimens.

Mutations in the phosphatase and tensin homologue (PTEN) and in proteins in the phosphatidylinositol-3-OH kinase signalling pathway are commonly observed molecular alterations in both indolent and aggressive prostate tumours, although, the precise mechanism through which they drive carcinogenesis is poorly understood.

Research by Sophia Tsai from Baylor College of Medicine, Houston, Texas, USA and her co-workers has now implicated a transcription factor, COUP-TFII, in promoting the growth and spread of prostate tumours.

This protein is already known to have a role in promoting tumour angiogenesis.

Tsai and her co-workers examined a panel of prostate tumours and normal prostate tissue for COUP-TFII expression, and found the transcription factor to be over-expressed in the tumour samples, most strongly in those from metastatic tumours.

High levels of COUP-TFII were also found to correlate clinically with a risk of early recurrence after radical prostatectomy.

The researchers then used a transgenic mouse model in which either PTEN; COUP-TFII; or both genes were conditionally knocked-out in prostate tissue to explore the causal link between transcription factor expression and tumour progression.

Mice with PTEN knocked out but intact COUP-TFII were found to develop advanced prostate tumours by five months of age, whereas all tumours in the double knockout mice remained low-grade and confined to the prostate epithelium at this stage.

In contrast, PTEN knockout (PTEN^-/-) mice in which COUP-TFII had been engineered to be over-expressed were found to rapidly develop highly aggressive, metastasis-prone prostate tumours.

Similar results were observed in mice over-expressing the transcription factor that were heterozygous for PTEN, but not in similar mice with normal PTEN expression levels.

The researchers analysed the transcriptomes of COUP-TFII depleted prostate cells,and found that genes known to be induced by TGF-b were more strongly expressed in these cells than in similar cells with normal COUP-TFII expression levels.

The TGF-b signalling pathway is known to be crucial for prostate cancer progression and it has been suggested that loss of PTEN expression upregulates TGF-b signalling, leading to the formation of a “growth barrier” that contains the tumours, preventing metastasis.  

Tsai and her co-workers therefore proposed that over-expression of COUP-TFII on a PTEN-null background enables prostate tumours to break through this barrier, leading to tumour growth and metastasis.

To test this hypothesis, they examined the gene expression profiles of primary tumour tissue from 596 patients who had died of prostate cancer for genes known to be regulated by COUP-TFII.

They found that high expression levels of this transcription factor and of genetic markers of its activity correlated with shorter survival times, although, interesting, not with shorter times to recurrence as measured by PSA levels.

Combining transcription levels of the COUP-TFII associated gene set with those of PTEN and other cell cycle directed signalling proteins including SMAD4 increased the predictive power above that for either gene set alone.

Furthermore, PTEN^-/- mice in which both SMAD4 and COUP-TFII expression had also been lost developed aggressive tumours like those with normal COUP-TFII expression levels.

Taken together, these results implicate the protein SMAD4 in inducing the tumour growth barrier that is generated when PTEN is lost, and that can be over-ridden by expression of COUP-TFII.

The protein COUP-TFII is a nuclear transcription factor that can be inhibited by small molecules, and these results further suggest that inhibitors of this protein might be useful as drugs to prevent progression of prostate cancer into an aggressive and potentially fatal disease.

Reference

Qin, J., Wu, S-P., Creighton, C.J. and 11 others (2012). COUP-TFII inhibits TGF-b-induced growth barrier to promote prostate tumourigenesis. Nature, published online ahead of print 28 November 2012. doi:10.1038/nature11674