The neu (also known as c-erb B2 or HER-2) oncogene was originally isolated from rat brain tumors induced by a chemical carcinogen, ethylnitrosourea. Detailed structural and functional analysis of the neu oncogene revealed that a single-point mutation occurring at the transmembrane domain of this oncogene was responsible for the conversion of the normal neu to the transforming neu oncogene. Significant sequence homology was identified between the neu oncogene-encoded p185 protein (p185neu) and epidermal growth factor receptor (EGFR), which led to the hypothesis that p185neu is a membrane growth-factor receptor of the EGFR superfamily. The neu gene amplification/overexpression is frequently observed in human solid tumors, including prostatic carcinoma, and is an attractive marker used to predict patient survival. In this proposal, we plan to extend our initial observations that: (1) the neu oncogene is expressed in both human prostatic carcinoma tissues and cell lines, and (2) the expression of this oncogene and a human prostate-specific antigen (PSA) by cultured androgen-responsive LNCaP cells and LNCaP tumors grown in vivo appears to be positively regulated by androgen. The following specific aims will be pursued: (1) to determine the steady- state mRNA and protein levels of neu, PSA and neuroendocrine cell- and endothelial cell-associated markers in fresh and archival normal and malignant human prostatic tissue specimens and to correlate the levels of expression of these variables with the tumor stage and grade and the survival of patients with primary and metastatic prostate cancers. The tissue specimens will be subjected to morphologic, biochemical, and molecular analyses to determine the levels and patterns of expression. The relationship between expressions of neu, PSA, and neuroendocrine cell- and endothelial cell-associated markers will be analyzed statistically. (2) to establish a rat prostatic cancer model by retroviral-mediated neu gene transfer technique for the analysis of the rate and pattern of prostatic cancer growth, progression, and potential metastasis. Male Nb rats will be injected with viral neu oncogene constructs in vivo. The prostate will be removed for histomorphologic analysis to determine the types of prostate tumor induced. The neu oncogene protein and mRNA expressions by the infected host cells will be analyzed by immunohistochemical and western blot analyses, and in situ hybridization and northern blot analyses, respectively. tumors expressing high, intermediate, and low levels of the neu oncogene will be selected for further biochemical and behavioral assessments. The expression levels of extracellular matrices such as fibronectin, collagen IV, laminin and heparin sulfate proteoglycans and growth factors such as aFGF, bFGF, EGF, and TGFs will be correlated with tumorigenicity and metastatic potential of the neu gene-infected cells.
| Pisters, L L; Troncoso, P; Zhau, H E et al. (1995) c-met proto-oncogene expression in benign and malignant human prostate tissues. J Urol 154:293-8 |
