Loss of SOX9 Expression Is Associated with PSA Recurrence in ERG-Positive and PTEN Deleted Prostate Cancers.

Christoph Burdelski,Waldemar Wilczak,Ronald Simon,Stefan Steurer,Thorsten Schlomm,Maria Christina Tsourlakis,Martina Kluth,Markus Graefen,Hans Heinzer,Till Krech,Guido Sauter,Corinna Wittmer,Claudia Hube-Magg,Patrick Lebok,Erzen Bujupi,Sarah Minner,Nathaniel Melling,Christina Koop,Zoran Culig

doi:10.1371/journal.pone.0128525

Abstract

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.

Highlights

Prostate cancer is the most prevalent cancer in men in Western societies [1]
The results of our study demonstrate that decreased, and not elevated, SOX9 protein expression is linked to poor prognosis and that this effect is strictly limited to the subset of prostate cancers harboring PTEN deletions
The results of our study show that a clinical relevance of SOX9 expression levels exists in prostate cancer that greatly depends on the molecular context of the tumor cells

Summary

Introduction

Prostate cancer is the most prevalent cancer in men in Western societies [1]. While most tumors have a rather indolent clinical course, prostate cancer still represents the third most common cause of cancer related death in men. Several lines of evidence exist that SOX9 might contribute to prostate cancer initiation and progression, including up-regulation during early stages of prostate neoplasia in mouse models [14], as well as in human prostatic intraepithelial neoplasia (PIN) [10] and prostate cancers [10,11] [14,15,16,17] Some of these studies on 98–387 patients have linked SOX9 overexpression to high-grade and advanced tumors [10,14,15,17], hormone-refractory disease state [15] or poor patient prognosis [14,15,17]

Methods

Results

Conclusion