Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer.
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.
Luo
Jun
J
Department of Pathology, Brady Urological Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
Zha
Shan
S
Gage
Wesley R
WR
Dunn
Thomas A
TA
Hicks
Jessica L
JL
Bennett
Christina J
CJ
Ewing
Charles M
CM
Platz
Elizabeth A
EA
Ferdinandusse
Sacha
S
Wanders
Ronald J
RJ
Trent
Jeffrey M
JM
Isaacs
William B
WB
De Marzo
Angelo M
AM
D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D015153:Blotting, Western; D004268:DNA-Binding Proteins; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000502:physiology; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019998:Racemases and Epimerases / Q000096:biosynthesis* / Q000235:genetics; D013194:Staining and Labeling / Q000379:methods; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
D014408:Biomarkers, Tumor; C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase