Identification of genes that are dysregulated in association with prostate
carcinogenesis can provide disease markers and clues relevant to disease etiology. Of particular interest as candidate markers of disease are those genes that are frequently overexpressed. In this study, we describe a gene,
alpha-methylacyl-CoA racemase (AMACR), whose expression is consistently up-regulated in
prostate cancer. Analysis of
mRNA levels of AMACR revealed an average up-regulation of approximately 9 fold in clinical
prostate cancer specimens compared with normal. Western blot and immunohistochemical analysis confirms the up-regulation at the
protein level and localizes the
enzyme predominantly to the peroxisomal compartment of
prostate cancer cells. A detailed immunohistochemical analysis of samples from 168 primary
prostate cancer cases using both standard slides and tissue microarrays demonstrates that both prostate
carcinomas and the presumed precursor lesion (high-grade
prostatic intraepithelial neoplasia) consistently scored significantly higher than matched normal prostate epithelium; 88% of the
carcinomas had a staining score higher than the highest score observed for any sample of normal prostate epithelium. Both untreated
metastases (n = 32 patients) and
hormone refractory
prostate cancers (n = 14 patients) were generally strongly positive for AMACR. To extend the utility of this marker for
prostate cancer diagnosis, we combined staining for cytoplasmic AMACR with staining for the
nuclear protein, p63, a basal cell marker in the prostate that is absent in
prostate cancer. In a simple assay that can be useful for the diagnosis of
prostate cancer on both biopsy and surgical specimens, combined staining for p63 and AMACR resulted in a staining pattern that greatly facilitated the identification of malignant prostate cells. The
enzyme encoded by the AMACR gene plays a critical role in peroxisomal beta oxidation of branched chain
fatty acid molecules. These observations could have important epidemiological and preventive implications for
prostate cancer, as the main sources of branched chain
fatty acids are dairy products and beef, the consumption of which has been associated with an increased risk for
prostate cancer in multiple studies. On the basis of its consistency and magnitude of
cancer cell-specific expression, we propose AMACR as an important new marker of
prostate cancer and that its use in combination with p63 staining will form the basis for an improved staining method for the identification of prostate
carcinomas. Furthermore, the absence of AMACR staining in the vast majority of normal tissues coupled with its enzymatic activity makes AMACR the ideal candidate for development of
molecular probes for the noninvasive identification of
prostate cancer by imaging modalities.