Abstract
Glycogen synthase kinase 3ß (GSK3ß) regulates many cancer relevant cellular processes and represents a potential therapeutic target. GSK3ß overexpression has been linked to adverse tumor features in many cancers, but its role in prostate cancer remains uncertain. We employed immunohistochemical GSK3ß expression analysis on a tissue microarray with 12,427 prostate cancers. Cytoplasmic and nuclear GSK3ß staining was separately analyzed. GSK3ß staining was absent in normal prostate epithelium, whereas 57% of 9,164 interpretable cancers showed detectable GSK3ß expression. Cytoplasmic staining was considered weak, moderate, and strong in 36%, 19.5% and 1.5% of tumors and was accompanied by nuclear GSK3ß staining in 47% of cases. Cytoplasmic GSK3ß staining as well as nuclear GSK3ß accumulation was associated with advanced tumor stage, high Gleason grade, presence of lymph node metastasis and early biochemical recurrence (p < 0.0001 each for cytoplasmic staining and nu-clear accumulation). Prognosis of GSK3ß positive cancers became particularly poor if nuclear GSK3ß staining was also seen (p < 0.0001). The prognostic impact of nuclear GSK3ß accumu-lation was independent of established preoperative and postoperative parameters in multivari-ate analyses (p < 0.0001). The significant association of GSK3ß expression with deletions of PTEN, 3p13 (p < 0.0001 each), 5q21 (p = 0.0014) and 6q15 (p = 0.0026) suggest a role of GSK3ß in the development of genomic instability. In summary, the results of our study identify GSK3ß as an independent prognostic marker in prostate cancer.
Highlights
Prostate cancer is the 2nd most prevalent cancer in men in Western societies [1], but only a small subset is highly aggressive and requires extensive treatment [2, 3]
Normal prostate tissue was negative for Glycogen synthase kinase 3ß (GSK3ß)
To better understand the prognostic impact of nuclear GSK3ß accumulation, we performed subset analyses in tumors with comparable classical and quantitative Gleason grades. These analyses revealed that nuclear GSK3ß expression measurement did provide additional prognostic impact in morphologically well-characterized tumors with Gleason 3+4 (p < 0.0001) and Gleason 4+3 (p = 0.0002, Figure 7A)
Summary
Prostate cancer is the 2nd most prevalent cancer in men in Western societies [1], but only a small subset is highly aggressive and requires extensive treatment [2, 3]. Overexpression of GSK3ß has been linked to adverse tumor phenotype and poor prognosis in several cancer types, including breast [6, 7], ovarian [8], oral cavity [9], urinary bladder [10], non-small cell lung [11], gastric [12], and pancreatic cancers [13]. Based on these findings, GSK3ß has gained considerable interest as a target for novel therapies. Two studies analyzing GSK3ß expression on clinical samples from 79 and 499 prostate cancer patients suggested associations between GSK3ß overexpression and high Gleason score [22] and potentially poor patient prognosis [15]
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