Heat shock protein expression independently predicts clinical outcome in prostate cancer

Heat shock proteins (hsps) occupy a central role in the regulation of intra cellular homeostasis, acid differential expression of individual hsps occur s in a broad range of neoplastic processes. This study was performed to tes t the hypothesis that the particular patterns by which individual hsps beco me specifically modulated in human prostate cancers are correlated with beh avioral phenotype and hence may be of value in determining the most appropr iate clinical management of individual patients. Monoclonal antibodies spec ific for each hsp protein were used to assess expression of hsp27, hsp60, a nd hsp70 in formalin-fixed, paraffin wax-embedded, archival tissue specimen s of early prostatic adenocarcinomas (pT(1-2)N(o)M(o)) removed at radical p rostatectomy (n = 25) and in advanced cancers (n = 95) identified at transu rethral resection of prostate (TURP), These findings were compared with sim ilar data from control prostates (n = 10) removed at primary cystectomy for urinary bladder neoplasia not involving the prostate and also at TURF for benign prostatic: hyperplasia (n = 50), Western blotting of whole cell lysa tes derived from established human prostatic epithelial cell lines PNT2, LN CaP, DU145, and PC3 was compared with expression of hsps by the primary hum an tissues. This study found that early irt situ neoplastic transformation of normal prostatic epithelium was consistently associated with loss of hsp 27 expression and that the level of hsp27 expression by individual prostate cancers was correlated with their Gleason grade. In advanced cancers, hsp2 7 expression was invariably associated with poor clinical outcome (P = 0.00 01), Data from cell lines supported the primary tissue findings, with eleva ted hsp27 expression only in aggressive malignant cell lines and androgen-i nsensitive cell lines. Expression of hsp60 was significantly increased in b oth early and advanced prostate cancer when compared with nonneoplastic pro static epithelium (P < 0.0001), as well as in malignant prostate cancer cel l lines. Expression of hsp70 was unaltered in early prostate cancers when c ompared with nonneoplastic prostatic epithelium but showed a diminished exp ression in morphologically advanced cancers (p = 0.0029). No consistent cor relation was found between levels of hsp60 or hsp70 expression and phenotyp ic behavior of individual primary prostatic cancers. Thus, patterns of hsp expression have been confirmed to be specifically and consistently modulate d in both early and advanced human prostate cancers, Whereas absence of hsp 27 is a reliable objective marker of early prostatic neoplasia, reexpressio n of this protein by an individual invasive prostatic carcinoma invariably heralds poor clinical prognosis, Because this protein has been shown to alt er the balance between proliferation and apoptosis, understanding the mecha nism(s) by which individual hsps regulate intracellular homeostasis may ass ist in explaining some key processes that occur during evolution of human p rostate cancers. We suggest that hsp27 expression provides novel diagnostic and prognostic information on individual patient survival which, if obtain ed at the time of primary diagnosis, would assist in determining tumor-spec ific management strategies. Development of techniques to therapeutically mo dulate hsp27 expression raises the possibility of novel targeted approaches to regulate this homeostatic mechanism, thus allowing better control over tumor cell proliferation and hence patient survival.