Abstract
Secreted frizzled-related protein 4 (SFRP4) controls WNT signaling and is thought to play a role for tumor aggressiveness. Here, we analyzed a tissue microarray containing 11,152 prostate cancers with pathological, clinical and molecular data by immunohistochemistry. SFRP4 expression was higher in cancer than in non-neoplastic acinar cells. SFRP4 staining was seen in 64.9% of tumors and classified as weak in 33.2%, moderate in 23.9% and strong in 7.8% of cancers. SFRP4 overexpression was linked to advanced tumor stage, high classical/quantitative Gleason grade (p < 0.0001 each), lymph node metastasis (p = 0.0002), and a positive surgical margin (p = 0.0017). SFRP4 positivity was markedly more frequent in ERG positive (77.4%) than in ERG negative cancers (57.4% p < 0.0001). Subset analyses in 2725 cancers with and 3592 cancers without TMPRSS2:ERG fusion revealed that associations with tumor phenotype and patient outcome were largely driven by the subset of ERG negative tumors. In a multivariate analysis including various postoperative and prognostic clinico-pathological features, SFRP4 protein expression emerged as an independent prognostic parameter in ERG negative cancers. SFRP4 immunostaining was significantly linked with 10 of 11 previously analyzed chromosomal deletions (p < 0.05 each). In conclusion, high SFRP4 immunostaining is associated with poor prognosis and genomic instability in ERG negative prostate cancers.
Highlights
In 2018 prostate cancer was the most common cancer in males in the majority of the countries of the world and the third most common cause of cancer related death [1]
The results of our analysis demonstrate that Secreted frizzled-related protein 4 (SFRP4) upregulation is an independent predictor of early Prostate specific antigen (PSA) recurrence in prostate cancers lacking TMPRSS2:ETS Transcription Factor ERG (ERG) fusions
Higher levels of SFRP4 staining in cancer glands as compared to adjacent normal prostate gland demonstrate that SFRP4 upregulations parallels prostate cancer development and progression
Summary
In 2018 prostate cancer was the most common cancer in males in the majority of the countries of the world and the third most common cause of cancer related death [1]. SFRP4 appears to play a role in prostate cancer, discrepant findings have been reported as to whether its loss or upregulation associates with disease progression. Studies found that SFRP4 overexpression was associated with a decreased rate of proliferation, decreased anchorageindependent growth, and decreased invasiveness in PC-3 and LNCaP cancer cells [16, 17], and that membranous SFRP4 expression was associated with good prognosis in 229 clinical prostate cancer specimens [16]. SFRP4 up-regulation was been found on the mRNA level in several studies [20,21,22,23,24] and SFRP4 is part of a commercial prostate cancer gene expression assay to estimate tumor aggressiveness [25]
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