Immunohistochemical analysis of rasGTPase activating protein (rasGAP) in prostate cancer

The ras protooncogene plays a key role in the signal transduction cascade of activated growth factors, and is known to be activated or overexpressed in multiple tumor types, including prostate cancer. rasGTPase activating protein (rasGAP), a major downregulator of ras activity, has been shown to be underexpressed in human trophoblastic tumors, and presumably acts as a tumor suppressor gene product in these neoplasms. To assess the role that rasGAP plays in the development of prostate cancer, we performed immunohistochemical analyses with anti rasGAP antibodies of 125 human prostate tumors from Israel. Staining results were correlated with Gleason grade. In the majority of tumors (99/125-79%) there was either no staining or the tumor and surrounding benign glands had a similar pattern of staining. In up to 16% of the tumors, cytoplasmic, tumor-specific loss of expression was noted, presumably indicative of the role of rasGAP as a tumor suppressor gene. Unexpectedly, in up to 21% of the tumors, nuclear staining was demonstrated, and in about 20% of these, there was an accompanying loss of expression in the non neoplastic cytoplasm. Neither cytoplasmic nor nuclear staining correlated with Gleason grade. These findings of nuclear staining by anti-rasGAP are intriguing, since it is the first time that nuclear translocation of rasGAP is demonstrated, which might indicate that in this subset of tumors, rasGAP acts as a direct acting oncogene. The data indicate that rasGAP may play a dual regulatory role in prostate proliferation and that nuclear expression of it may be associated with malignant transformation of these cells.