The
transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate
carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in
prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152
prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in
luminal cells of normal prostate glands (50% SOX9 positive) and 3,671
cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive), but was markedly increased in 3,116 ERG-fusion positive
cancers (81% SOX9 positive, p<0.0001). While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative
cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG-positive
cancers (p<0.0001 each). SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive
tumors harboring PTEN deletions (p=0.001), but had no significant effect in ERG-negative
cancers or in
tumors with normal PTEN copy numbers. In summary, the results of our study argue against a
tumor-promoting role of SOX9 in
prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive
cancers harboring PTEN deletions.