alpha-Methylacyl-CoA racemase: expression levels of this novel cancer biomarker depend on tumor differentiation.
Journal: 2002/September - American Journal of Pathology
ISSN: 0002-9440
PUBMED: 12213712
Abstract:
alpha-Methylacyl-CoA racemase (AMACR) has previously been shown to be a highly sensitive marker for colorectal and clinically localized prostate cancer (PCa). However, AMACR expression was down-regulated at the transcript and protein level in hormone-refractory metastatic PCa, suggesting a hormone-dependent expression of AMACR. To further explore the hypothesis that AMACR is hormone regulated and plays a role in PCa progression AMACR protein expression was characterized in a broad range of PCa samples treated with variable amounts and lengths of exogenous anti-androgens. Analysis included standard slides and high-density tissue microarrays. AMACR protein expression was significantly increased in localized hormone-naive PCa as compared to benign (P < 0.001). Mean AMACR expression was lower in tissue samples from patients who had received neoadjuvant hormone treatment but still higher compared to hormone-refractory metastases. The hormone-sensitive tumor cell line, LNCaP, demonstrated stronger AMACR expression by Western blot analysis than the poorly differentiated cell lines DU-145 and PC-3. AMACR protein expression in cells after exposure to anti-androgen treatment was unchanged, whereas prostate-specific antigen, known to be androgen-regulated, demonstrated decreased protein expression. Surprisingly, this data suggests that AMACR expression is not regulated by androgens. Examination of colorectal cancer, which is not hormone regulated, demonstrated high levels of AMACR expression in well to moderately differentiated tumors and weak expression in anaplastic colorectal cancers. Taken together, these data suggest that AMACR expression is not hormone-dependent but may in fact be a marker of tumor differentiation.
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Am J Pathol 161(3): 841-848

α-Methylacyl-CoA Racemase: Expression Levels of this Novel Cancer Biomarker Depend on Tumor Differentiation

+4 authors
From the Departments of Pathology, Urology, and Biostatistics, and the Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and the Departments of Pathology and Urology, Faculty of Medicine, University of Ulm, Ulm, Germany
Accepted 2002 May 15.

Abstract

α-Methylacyl-CoA racemase (AMACR) has previously been shown to be a highly sensitive marker for colorectal and clinically localized prostate cancer (PCa). However, AMACR expression was down-regulated at the transcript and protein level in hormone-refractory metastatic PCa, suggesting a hormone-dependent expression of AMACR. To further explore the hypothesis that AMACR is hormone regulated and plays a role in PCa progression AMACR protein expression was characterized in a broad range of PCa samples treated with variable amounts and lengths of exogenous anti-androgens. Analysis included standard slides and high-density tissue microarrays. AMACR protein expression was significantly increased in localized hormone-naive PCa as compared to benign (P < 0.001). Mean AMACR expression was lower in tissue samples from patients who had received neoadjuvant hormone treatment but still higher compared to hormone-refractory metastases. The hormone-sensitive tumor cell line, LNCaP, demonstrated stronger AMACR expression by Western blot analysis than the poorly differentiated cell lines DU-145 and PC-3. AMACR protein expression in cells after exposure to anti-androgen treatment was unchanged, whereas prostate-specific antigen, known to be androgen-regulated, demonstrated decreased protein expression. Surprisingly, this data suggests that AMACR expression is not regulated by androgens. Examination of colorectal cancer, which is not hormone regulated, demonstrated high levels of AMACR expression in well to moderately differentiated tumors and weak expression in anaplastic colorectal cancers. Taken together, these data suggest that AMACR expression is not hormone-dependent but may in fact be a marker of tumor differentiation.

Abstract

Prostate cancer (PCa) is the most common non-skin cancer diagnosed in men in the United States. 1 One explanation for the rapid increase in the incidence of PCa diagnosis has been the advent of prostate-specific antigen (PSA) screening. PSA screening has led to earlier detection of PCa. 2 However, the impact of PSA screening on cancer-specific mortality is still unknown pending the results of prospective randomized screening studies. 3-5 A major limitation of the serum PSA test is lack of PCa sensitivity and specificity especially in the intermediate range of PSA detection (4 to 10 ng/ml). Our group has concentrated on developing and validating novel PCa biomarkers using a combined expression and tissue microarray (TMA) approach. 6 This approach by our group and others has led to the identification of hepsin, a serine protease up-regulated in PCa. 6-10 Furthermore, our group was able to use high-density TMAs to determine associations of hepsin protein and another protein, pim-1 kinase, with clinical outcome. 6

Using a similar approach, α-methylacyl-CoA racemase (AMACR), an enzyme that plays an important role in bile acid biosynthesis and β-oxidation of branched-chain fatty acids, 11,12 was also recently identified. AMACR was determined to be up-regulated in PCa after examination of several independent gene expression data sets, including our own. 6,8,10,13 These findings were supported by different groups on the protein level even when using different types of antibodies for immunoblot analysis and high-density TMAs. 13-15 Interestingly, hormone-refractory metastatic PCa demonstrated lower AMACR expression than hormone-naive-localized PCa. This observation suggested that AMACR protein expression is regulated by androgens. It is extremely important to identify PCa biomarkers, which portend an aggressive clinical course, given that hormone-refractory tumors are virtually all lethal. However, currently no clinical marker is available to identify a subgroup of localized tumors that may eventually develop into lethal PCa. To examine the intriguing possibility that the PCa biomarker, AMACR, might play a role in hormone dysregulation of localized PCa, we undertook the current study.

Acknowledgments

We thank Dr. Ronald J. A. Wanders (University of Amsterdam) for the anti-AMACR antibody; Robin Kunkel with assistance in preparing figures; Dr. Henry D. Appelman (Pathology, University of Michigan) for pathology support; Prof. Dr. Peter Möller, Chairman Department of Pathology, Ulm, Germany, for providing tissue samples; and Dr. Kenneth J. Pienta, Associate Professor, University of Michigan, for his support through the Rapid Autopsy Program and the SPORE affiliation.

Acknowledgments

Footnotes

Address reprint requests to Mark A. Rubin, M.D., Department of Pathology, University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-0602. E-mail: .ude.hcimu@niburam

Supported by the Specialized Program in Research Excellence in Prostate Cancer (P50 CA69568), the National Cancer Institute, and the University of Michigan Bioinformatics Program (pilot grant 379206).

Footnotes

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