Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

Abstract

Background: This study was performed to test the hypothesis that expression of small heat shock protein Hsp-27 is, at diagnosis, a reliable predictive biomarker of clinically aggressive prostate cancer.

Methods: A panel of tissue microarrays constructed from a well-characterised cohort of 553 men with conservatively managed prostate cancer was stained immunohistochemically to detect Hsp-27 protein. Hsp-27 expression was compared with a series of pathological and clinical parameters, including outcome.

Results: Hsp-27 staining was indicative of higher Gleason score (P<0.001). In tissue cores having a Gleason score >7, the presence of Hsp-27 retained its power to independently predict poor clinical outcome (P<0.002). Higher levels of Hsp-27 staining were almost entirely restricted to cancers lacking ERG rearrangements (chi2 trend=31.4, P<0.001), although this distribution did not have prognostic significance.

Interpretation: This study has confirmed that, in prostate cancers managed conservatively over a period of more than 15 years, expression of Hsp-27 is an accurate and independent predictive biomarker of aggressive disease with poor clinical outcome (P<0.001). These findings suggest that apoptotic and cell-migration pathways modulated by Hsp-27 may contain targets susceptible to the development of biologically appropriate chemotherapeutic agents that are likely to prove effective in treating aggressive prostate cancers.

Figure 1

Immunohistochemical expression of Hsp-27 in TMA cores of prostatic tissues. The location of the high-magnification regions shown below each of the cores is indicated by the corresponding rectangular field. Stromal expression was not identified in any of the malignant tissues examined. No expression of Hsp-27 was identified in the nuclei although the amounts may be below the level of immunohistochemical detection. (A) Normal prostatic tissue in which luminal epithelial cells express Hsp-27 within the cytoplasm. Basal cells are scanty but, where present, are also stained. Stromal tissues are not stained. (B) Hyperplastic but not dysplastic glandular epithelium strongly expressing Hsp-27 within the cytoplasm. (C) Hyperplastic and mildly dysplastic epithelium in which basal cells are prominent and uniformly express Hsp-27. The overlying luminal epithelial cells are mainly negative, although a few express Hsp-27 strongly. (D) Hyperplastic, dysplastic and focally neoplastic intra-glandular epithelium that is predominantly negative for Hsp-27. Occasionally small foci of basal and luminal epithelial cells strongly express Hsp-27. (E) Moderately differentiated (Gleason 3+3) prostatic adenocarcinoma that is negative for Hsp-27 expression. (F) Moderately differentiated (Gleason 3+3) prostatic adenocarcinoma expressing Hsp-27 at a low level (+) in the cytoplasm of the majority of the malignant cells. (G) Poorly differentiated (Gleason 4+3) prostatic adenocarcinoma expression of Hsp-27 at a high (+++) level in the cytoplasm of the majority of the malignant cells. (H) Very poorly differentiated (Gleason 5+5) prostatic adenocarcinoma heterogeneously expressing Hsp-27 at an intermediate level (++) in the majority, but not all of the malignant cells. Magnification of all cores: × 60. The detailed fields within each of the cores are magnified at × 200.

Figure 2

Numerical distribution of Hsp-27 expression by the epithelial cells in normal, hyperplastic, PIN and malignant tissues (cancer cores). The clinical behaviour of the malignant cells expressing Hsp-27 is shown in Figure 3. The +, ++ and +++ signs are a conventional semi-quantitative assessment of the amount of staining defined in Figure 1 legend.

Figure 3

(A) Prostate cancer survival and (B) overall survival according to Hsp-27 expression.

Figure 4

Forest plots indicating the effect of hazard ratios of Hsp-27 expression on prostate cancer survival in a Cox multivariate model by (A) Gleason subgroups and (B) ETS subgroups. The graph shows for each subgroup the hazard ratio with the 95% confidence interval and the percentage weight contributed to the meta-analysis by each subgroup is shown by the size of the corresponding rectangle. The summary hazard ratio is shown by the solid line and the middle of the diamond, the extremes of which represent the 95% confidence intervals. The dotted line shows the no effect point.