ABSTRACT
OBJECTIVE: To investigate molecular alterations associating with prostate carcinoma progression and potentially provide information toward more accurate prognosis/diagnosis. METHODS: A set of laser captured microdissected (LCM) specimens from 300 prostate cancer (PCa) patients undergoing radical prostatectomy (RP) were defined. Ten patients representing "aggressive" PCa, and 10 representing "non-aggressive" PCa were selected based on prostate-specific antigen (PSA) recurrence, Gleason score, pathological stage and tumor cell differentiation, with matched patient age and race between the two groups. Normal and neoplastic prostate epithelial cells were collected with LCM from frozen tissue slides obtained from the RP specimens. The expressions of a panel of genes, including NPY, PTEN, AR, AMACR, DD3, and GSTP1, were measured by quantitative real-time RT-PCR (TaqMan), and correlation was analyzed with clinicopathological features. RESULTS: The expressions of AMACR and DD3 were consistently up-regulated in cancer cells compared to benign prostate epithelial cells in all PCa patients, whereas GSTP1 expression was down regulated in each patient. NPY, PTEN and AR exhibited a striking difference in their expression patterns between aggressive and non-aggressive PCas (P=0.0203, 0.0284, and 0.0378, respectively, Wilcoxon rank sum test). The lower expression of NPY showed association with "aggressive" PCas based on a larger PCa patient cohort analysis (P=0.0037, univariate generalized linear model (GLM) analysis). CONCLUSION: Despite widely noted heterogeneous nature of PCa, gene expression alterations of AMACR, DD3, and GSTP1 in LCM-derived PCa epithelial cells suggest for common underlying mechanisms in the initiation of PCa. Lower NPY expression level is significantly associated with more aggressive clinical behavior of PCa; PTEN and AR may have potential in defining PCa with aggressive clinical behavior. Studies along these lines have potential to define PCa-associated gene expression alterations and likely co-regulation of genes/pathways critical in the biology of PCa onset/progression.
Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Neuropeptide Y/genetics , Prostatic Neoplasms/genetics , Antigens, Neoplasm/genetics , Glutathione S-Transferase pi/genetics , Humans , Male , PTEN Phosphohydrolase/genetics , Prostatic Neoplasms/pathology , RNA, Messenger/genetics , Racemases and Epimerases/genetics , Receptors, Androgen/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity , Time FactorsABSTRACT
Loss of heterozygosity (LOH) in the 10q21 region that harbors the tumor suppressor gene ANX7-GTPase gene have been found in 35% of prostate tumors. Therefore, the rationale for this study is that this gene could also be implicated in breast pathogenesis as well. We investigated allelic losses in microsatellites of the 10q21 region, and their correlations with ANX7 status, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 status and pathological phenotype in 30 breast carcinomas with matched control specimens. The LOH analysis was performed by amplifying DNA by PCR, using four markers of the 10q21 region (AFMa299ya5, AFM220xe5, AFM 063xc5, AFM200wf4). LOH in at least one marker of the 10q21 region (AFM220xe5 marker close to ANX7) was found in 66% of the first set of informative tumors containing 10 pairs of specimens. Subsequent comparison between 20 carcinomas using AFM220xe5, with and without LOH in terms of pathological parameters showed significant associations with differences in age (P = 0.04) ER (P = 0.05) Ki-67 (P = 0.04) and PR (P = 0.01) a trend toward significance was found for tumor size (P = 0.06) and histological grade III (P = 0.06). These results suggest that the ANX7 gene, or other genes of the 10q21 region, could be functionally related to breast cancer, probably influencing the hormone receptor expression associated with poor prognosis during development.
