gms | German Medical Science

Background: Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesis-specific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet.

Methods: In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry, using an antibody recognizing all three Rac isoforms. Moreover, representative tissue samples were analyzed for Rac expression by isoform-specific Real-Time PCR. Immunohistochemically obtained results were compared to different histopathological characteristics of prostate cancer and disease-free survival.

Results: By immunohistochemistry, Rac proteins were significantly stronger expressed in both HG-PIN (p<0.001) and prostate carcinomas (p<0.001) when compared to benign secretory epithelium. Accordingly, 6 out of 7 tumor tissues exhibited higher RNA expression levels of Rac1 and/or Rac3than the respective normal counterparts. Increased protein expression of Rac in prostate carcinomas relative to benign secretory epithelium was statistically significantly associated with the presence of perineural invasion (P=0.005) and with disease recurrence (P=0.041). Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (P=0.0375), preoperative prostate-specific antigen levels (P=0.0457), pT stage (P=0.0016), and Gleason score (P=0.0008) with decreased disease-free survival. Most importantly, this prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all of these four factors (relative risk [RR]= 3.27, 95% confidence interval [CI]= 1.09-9.83; P=0.035).

Conclusions: Our data suggest that increased Rac protein expression is an early event in prostate cancer development and that Rac protein overexpression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased disease-free survival.