Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer. 1195 72

The present study documents that stabilization of beta-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized beta-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of beta-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating beta-catenin expressing basal cells. Our observations indicate that beta-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate.
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PMID:Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia. 1203 66

Prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface antigen expressed in normal prostate and associated with human and murine prostate cancer. To begin to investigate a possible link between PSCA expression in normal prostate and prostate carcinogenesis, we characterized the phenotype and proliferative behavior of normal PSCA-expressing prostate epithelial cells (PrEC) in tissue culture. PSCA was expressed in a subset of prostate epithelial cells that coexpress basal and secretory cytokeratins. PSCA-positive cells were the direct progeny of PSCA-negative cells and were characterized by a more differentiated morphology and a slower proliferative rate than PSCA-negative cells. Although PSCA-positive cells continued to express basal cell markers such as CD44, they lost expression of the basal cell marker p63. In contrast, expression of prostate specific antigen and androgen receptor transcripts was detectable in PSCA-positive PrEC. These findings suggest that PSCA is a unique marker of an intermediate subpopulation of PrEC in transition from a basal to a terminally differentiated secretory phenotype and may be a useful marker for the study of normal and malignant prostate development.
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PMID:Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells. 1249 58

p63 expression was evaluated in a tissue microarray of prostate tissues including benign glands, prostatic intraepithelial neoplasia and prostatic carcinoma. Immunostaining with anti-p63 antibody was restricted to basal cell nuclei. Detectable p63 was found in immortalized and early passage cell cultures, but not in senescent cultures or metastatic tumor-derived cell lines. The selective presence of p63 in basal cells of the prostate suggests that p63 can be used as a marker of basal cells and in vitro typing cell cultures of prostate cancer (CaP). The basal cell association underscores its critical functions in the biology of basal cells.
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PMID:p63 expression profile in normal and malignant prostate epithelial cells. 1255

Antibodies against high molecular weight cytokeratin (34betaE12) and p63 are frequently used basal cell markers to aid in the diagnosis of prostate cancer (Pca). Absence of a basal cell marker in an atypical lesion histologically suspicious for cancer supports a diagnosis of Pca. However, absence of basal cells demonstrable by basal cell immunohistochemistry (IHC) is not always conclusive for PCa. Some benign prostatic lesions may have inconspicuous or even lack basal cell lining focally. Technical factors such as tissue fixation and antigen retrieval techniques may also make the detection of basal cells difficult. Improving the sensitivity of current basal cell markers is critical if these tests are being used to help make diagnostic decisions in conjunction with standard histology. In this study, we test the hypothesis that that inclusion of both 34betaE12 and p63 in the same IHC reaction (basal cell cocktail) is advantageous over either marker used alone. One thousand three hundred fifty glands from 9 trans-urethral resectioned of prostate specimens with benign prostatic hypertrophy were used to study the immunostaining intensity and pattern for 34betaE12, p63, and the basal cell cocktail. Basal cell marker expression was scored as strong, moderate, weak, or negative. Basal cell staining was considered complete if 75% of the gland's circumference was positive for the basal cell marker and partial if <25% of the circumference was stained. The mean staining intensity and variance were calculated for 34betaE12, p63, and the basal cell cocktail. A paired test was used to evaluate whether the overall basal cell staining was significantly different between 34betaE12, p63, and the basal cell cocktail. F-test was used to assess the variances for 34betaE12, p63, and the basal cell cocktail. A high-density tissue microarray (TMA) comprising prostate tissue from 103 tumors from men with clinically localized Pca and a separate TMA comprising metastatic hormone-refractory Pca samples from 23 rapid autopsy cases were used to study the aberrant expression of 34betaE12 and p63 in clinically localized and poorly differentiated Pca. The prostate glands in transition zone have variable basal cell staining intensity and pattern with 34betaE12, p63, or the cocktail. Histologically, benign glands lack basal cell lining in 2%, 6%, and 2% of glands with cocktail, 34betaE12, and p63 staining, respectively. The staining variance for the cocktail is significantly smaller than that for 34betaE12 (0.0100 vs 0.1559, p = 0.0008). It is also smaller than that for p63, although a statistical significance has not been reached (0.0100 vs 0.0345, p = 0.099). The basal cell cocktail stains the basal cell layers more intensely than either 34betaE12 or p63 alone, with complete and partial strong basal cell staining in 93% and 1% of benign glands, compared with 55% and 4% with 34betaE12 and 81% and 1% with p63. Complete and partial weak staining is seen in 0% and 0% of benign glands with basal cell cocktail, compared with 8% and 7% with 34betaE12 and 4% and 1% with p63 (p = 0.007 and 0.014 for cocktail vs 34betaE12 and cocktail vs p63, respectively). A total of 2.8% clinically localized Pca had positive 34betaE12 staining and 0.3% had positive p63 staining. Five (22%) of the metastatic Pca is positive for 34betaE12. However, none had p63 expression. The basal cell cocktail had a staining pattern identical to that of 34betaE12. IHC of the prostatic glands from the transition zone is subjected to staining variability that results in frequent variable and occasional negative basal cell staining in histologically benign glands; 34betaE12 is most susceptible, and basal cell cocktail is least susceptible to such variability. Basal cell cocktail not only increases the sensitivity of the basal cell detection, but also reduces the staining variability and therefore renders the basal cell immunostaining more consistent. We recommend this basal cell cocktail for routine Pca diagnostic work-up.
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PMID:Basal cell cocktail (34betaE12 + p63) improves the detection of prostate basal cells. 1260 93

Within the human prostate epithelium four cell populations can be discriminated based on their expression of keratins (K). Basal cells express high levels of K5 and K14, as well as p63, whereas they have very low levels of androgen receptor, prostate-specific antigen (PSA), K8, and K18. Luminal secretory cells lack p63, K5, and K14 but express high levels of K8, K18, androgen receptor, and PSA. Additionally, cells have been identified with a keratin phenotype intermediate between basal and luminal cells that co-express high levels of K5 and K18 (K5/18) as well as hepatocyte growth factor receptor c-MET. Although intermediate cells have been proposed as precursor cells of prostate cancer, their biology is ill defined. Epithelial cells in proliferative inflammatory atrophy (PIA) appear to be cycling rapidly as indicated by expression of Ki-67, and morphological transitions have been identified between PIA and high-grade prostate intraepithelial neoplasia. Many of the atrophic epithelial luminal cells in PIA are candidates for intermediate cells based in part on weak expression of PSA and androgen receptor, high levels of K8/18, and lack of p63. The objective of this study was to further clarify the phenotype of the proposed intermediate cells in PIA and to quantitatively determine the level in which these intermediate cells preferentially occur in PIA lesions. Intermediate cells were immunohistochemically demonstrated using antibodies to K5, K14, K18, and c-MET. Using radical prostatectomy specimens (n = 15) the area fraction of intermediate cells in normally differentiated prostate epithelium and PIA were quantified by a grid point counting method. Atrophic luminal cells of PIA lesions expressed K5 in 39.2 +/- 7.4% of cells compared to 2.4 +/- 2.3% in normal epithelium (P < 0.00001). By contrast, K14 was only expressed in 3.0 +/- 3.2% of the luminal cells. Previous studies have shown that virtually 100% of these atrophic luminal cells are strongly positive for K8/18. c-MET was present in 44.1 +/- 14.1% of luminal cells in PIA but only in 2.1 +/- 2.8% of luminal cells in normal epithelium (P < 0.00001). To unambiguously determine whether intermediate luminal cells in PIA show increased proliferative activity and decreased p27(kip1) expression, double-staining immunofluorescence of Ki-67 and K5, as well as p27(Kip1) and K5 was performed. Luminal cells in PIA often co-expressed K5 and Ki-67. Although p27(Kip1) was strongly expressed in K5-negative differentiated cells in normal epithelium, p27(Kip1) staining was absent in many of the K5-positive cells in the luminal compartment of PIA. We conclude that cells phenotypically intermediate between basal and secretory cells are enriched in PIA lesions. The finding of a large number of highly proliferating intermediate cells in PIA provides further support that these cells may serve as preferred target cells in prostate carcinogenesis.
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PMID:Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy. 1270 36

Foamy gland and pseudohyperplastic carcinomas are two uncommon variants of prostate cancer and often pose diagnostic challenges on needle biopsies. Alpha-methylacyl-CoA-racemase (AMACR) is a recently discovered tumor marker whose expression is significantly upregulated in prostate cancer. However, the original works only studied ordinary prostate cancer without reference to specific morphologic variants. Therefore, the expression and diagnostic utility of AMACR in specific variants of prostate cancer are unknown. In addition, two different antibodies, one monoclonal and one polyclonal, were used in the previous studies. The goal of this study is to examine the expression pattern and diagnostic utility of AMACR in foamy gland and pseudohyperplastic prostate cancer and to compare the diagnostic utility of the two anti-AMACR antibodies in the same prostate needle biopsy series. Prostate cancer with foamy gland or pseudohyperplastic features was retrieved from the Johns Hopkins Hospital Surgical Pathology file. Thirty needle biopsies harboring prostate cancer with foamy gland features and 17 needle biopsies harboring prostate cancer with pseudohyperplastic features were available for this study. Immunohistochemistry for AMACR was performed with two antibodies, a monoclonal one (P504S) and a polyclonal one (AMACR-p), using previously published protocols. Immunohistochemistry for high molecular weight cytokeratin and p63 was performed to confirm the cancer diagnosis. The AMACR staining intensity was graded as negative, weak, moderate, and strong. Only the staining that was significantly stronger than that of background benign glands was considered positive. A total of 68% and 62% of foamy gland prostate cancer was positive for AMACR with P504S and AMACR-p antibodies, respectively. A total of 77% and 70% of pseudohyperplastic prostate cancer was positive for AMACR with P504S and AMACR-p antibodies, respectively. Staining was often heterogeneous with different staining intensities within the same lesion. The mean percentage of stained glands in positive cases was 74.4% (range 25-100%) with P504S and 78.9% (range 20-100%) with AMACR-p in foamy gland prostate cancer and 91% (range 10-100%) with P504S, and 86.7% (range 10-100%) with AMACR-p in pseudohyperplastic prostate cancer. Seven foci of high-grade prostatic intraepithelial neoplasia present in the study cases were all positive for AMACR. The two antibodies were not statistically different in their sensitivity and specificity. In conclusion, AMACR is potentially a useful diagnostic marker for foamy gland and pseudohyperplastic prostate cancer in the following setting. When the pathologist favors the diagnosis of these variants of cancer on routine stained sections and stains for basal cells are negative, yet still a definitive diagnosis of cancer is difficult because of the cancers' deceptively benign appearance, positive staining for AMACR can provide the additional confidence to establish a definitive malignant diagnosis. The major caveat in the interpretation of positive staining is that high-grade prostatic intraepithelial neoplasia cannot be in the differential diagnosis.
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PMID:Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer. 1276 80

Basal cell proliferation is a common finding in a benign hyperplastic prostate gland. Occasionally, basal cell hyperplasia is so florid that it can be mistaken for prostatic adenocarcinoma. We characterized histological, ultrastructural, and immunohistochemical features of florid basal cell hyperplasia from transurethral resections (n = 11) and prostatectomy specimens (n = 4). Fifteen cases of prostatic adenocarcinoma were used as comparison. Intraluminal calcification was present in 40% of florid basal cell hyperplasia cases (6 of 15) and a unique finding of intracytoplasmic hyaline globules was detected in 53.3% of florid basal cell hyperplasia cases (8 of 15). Ultrastructural analysis revealed luminal calcification and intracytoplasmic electron-dense globules in foci of basal cell hyperplasia. Crystalloids, a frequent finding in low-grade prostate cancer, were absent in all 15 cases of florid basal cell hyperplasia. By immunohistochemistry, the basal cell-specific 34betaE12 and p63 as well as glutathione-s-transferase pi were positive in all basal cell hyperplasia cases but negative in all prostatic adenocarcinomas. These distinguishing features of florid basal cell hyperplasia are helpful in differential diagnosis from prostatic adenocarcinoma. Cytokeratins 8 and 18 were both positive in basal cells, benign secretory cells, and carcinoma cells, failing to be of discrimatory value. Immunostaining for alpha-methylacyl-coenzyme racemase, a new prostate cancer marker, was negative in hyperplastic basal cells but detected a distinct minor benign cell population in basal cell hyperplasia of possible neuroendocrine origin.
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PMID:Florid basal cell hyperplasia of the prostate: a histological, ultrastructural, and immunohistochemical analysis. 1279 20

Expression of the alpha-methylacyl-CoA racemase (AMACR) gene has recently been demonstrated by several groups to be markedly elevated in prostate cancer cells with little expression in benign prostate tissue and has been suggested as a molecular marker of prostate cancer on needle biopsy. There is scant data, however, as to the sensitivity and specificity of AMACR in the diagnosis of small foci of cancer on needle biopsy. A total of 209 needle biopsies of the prostate with small foci (<5% of a core) of prostatic adenocarcinoma were identified. A total of 175 cases were received in consultation by one of the authors (140 from a single institution and 35 from different outside institutions) and 34 cases were from our hospital file. Immunohistochemistry for high molecular weight cytokeratin and p63 was performed in all cases to confirm the diagnosis of cancer. Only AMACR staining that was significantly stronger than that of background benign glands was considered positive; 88% of all cases of prostate cancer were positive for AMACR. The sensitivity varied among the different groups: 100% for the in house cases, 87.1% for the cases from a single institution, and 80% for cases from different outside institutions. The mean percentage of stained glands in positive cases was 95.9%, with 150 (71.8%) cases showing 100% of the glands positive and 25 (12.0%) cases showing no staining. Because negative staining for basal cell markers, especially in a small focus of atypical glands, is not necessarily diagnostic of prostate cancer, positive staining for AMACR can increase the level of confidence in establishing a definitive malignant diagnosis. However, the sensitivity of AMACR staining may vary in specimens from different pathology laboratories, possibly related to differences in fixation and processing. It is important to optimize the staining technique for each laboratory and recognize that some small cancers on needle biopsy may be AMACR negative.
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PMID:Alpha-methylacyl-CoA racemase: a variably sensitive immunohistochemical marker for the diagnosis of small prostate cancer foci on needle biopsy. 1288 45

Prostate cancer is among the most common malignancies. It is estimated that 1 in 6 men in the United States will be diagnosed with this disease. Despite the high prevalence and importance of prostate cancer, the molecular mechanisms underlying its development and progression remain poorly understood. This article reviews new information about the roles of oxidants and electrophiles in prostate cancer; the potential importance of chronic inflammation and atrophy in prostate carcinogenesis, and implications for chemoprevention; evidence supporting telomere shortening and genetic instability in the etiology of prostate cancer; and alpha-methylacyl-coenzyme A racemase (AMACR) as a potential marker for prostate carcinogenesis. These new results show that at least some high-grade prostatic intraepithelial neoplasias (PIN) and early adenocarcinomas appear to arise from proliferative inflammatory atrophy (PIA). Inflammation and other environmental factors may lead to the destruction of prostate epithelial cells, and increased proliferation may occur as a response to this cell death. Such proliferation may be mechanistically related to decreased p27(Kip1) observed in PIA. The decreased apoptosis associated with these events may also be related to increased expression of Bcl-2. Increased oxidant and electrophile stress in the setting of increased proliferation associated with these events may lead to elevated glutathione S-transferase P1 (GSTP1) expression as a genomic-protective measure. However, aberrant methylation of the CpG island of the GSTP1 gene promoter silences GSTP1 gene expression and protein levels, setting the stage for additional genetic damage and accelerated progression toward PIN and carcinoma. Additional results show that AMACR may be an important new marker of prostate cancer, and its use in combination with p63 staining may provide the basis for an improved method for identification of prostate cancer.
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PMID:Human prostate cancer precursors and pathobiology. 1460 18


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