High level expression of glucocorticoid receptor (GR) is linked to aggressive tumor features, early biochemical recurrence, and genetic instability in prostate cancer

TL;DR

High levels of the glucocorticoid receptor in prostate cancer are linked to more aggressive disease and worse outcomes, suggesting it could help identify high-risk patients.

Contribution

This study demonstrates that GR expression is an independent prognostic marker for aggressive prostate cancer features and poor outcomes.

Findings

High GR staining is strongly associated with advanced tumor stage, high Gleason grade, and early recurrence.

Strong GR expression is independently predictive of poor prognosis, regardless of other clinical factors.

High GR expression correlates with TMPRSS2:ERG fusion and androgen receptor status, worsening patient outcomes.

Abstract

The glucocorticoid receptor (GR) is a nuclear receptor protein for cortisol and other glucocorticoids and regulates the transcription of thousands of genes involved in metabolism, development, stress and inflammatory response. In prostate cancer, GR may confer resistance to anti-androgen receptor therapies by bypassing AR blockade. However, only few data are available on the prognostic role of GR expression in prostate cancer.

To estimate the prognostic value of GR, a tissue microarray containing 17,747 prostate cancers with associated follow-up and molecular data was analyzed by immunohistochemistry.

All patients had undergone radical prostatectomy. GR immunostaining was found in 10,832 (89.1%) of 12,125 interpretable tumors, including 48.5% with weak, 29.8% with moderate and 11% with strong staining intensity. Increased GR staining was strongly linked to adverse feature of the disease, including high tumor stage (pT), high classical and quantitative Gleason grade, presence of nodal metastases (pN+), a positive surgical margin (R1) status, and early biochemical recurrence (p < 0.0001 each). A multivariate analysis showed that the prognostic value of strong GR staining was independent of pT, Gleason grade, pN and R status. High level GR staining was significantly linked to TMPRSS2:ERG fusion (p < 0.0001) and high androgen receptor expression (p < 0.0001 each). A combined analysis of the impact of GR and AR on patient prognosis identified the best prognosis for ARneg/GRneg cancers while ARpos/GRpos cancers showed the worst prognosis (p < 0.0001). Moreover, high GR expression was a strong predictor of poor prognosis in AR low, AR intermediate and AR high cancers (p < 0.0001 each).

High level expression of GR is strongly linked to prostate cancer aggressiveness in uni- and multivariate analysis. GR immunohistochemistry – alone or in combination with other markers – holds great potential to identify patients with a high risk for tumor progression.

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