Faculty Bibliography

The determination of tissue thickness in paraffin blocks in the histology laboratory has been largely based on visual estimates. More accurate methods are required for the construction of tissue microarrays (TMAs) to assure a greater yield of cores in sections through the TMA block. We describe an accurate radiographic method to determine tissue thickness in donor paraffin blocks and have validated its application to TMA construction. Individual radiographic analysis was performed on paraffin donor blocks used for the construction of TMAs for determination of donor block tissue thickness. Consecutive numbered slide sections through the TMA block were then examined for the presence or loss of cores in the 150th TMA slide (from the final third of the TMA block) and correlated with the thickness of the individual donor blocks determined radiographically. At the 150th TMA slide, 202 of 1340 cores (15.1%) were depleted. Radiographic measurement showed a greater thickness of the donor paraffin block tissue (2.02 mm) corresponding to the retained cores as compared with the donor tissue (1.54 mm) of the depleted cores (P < 0.001). With progressive slide sections through a TMA block, the retention of tissue cores shows a significant correlation with donor block tissue thickness. Radiographic determination of tissue thickness in donor paraffin blocks can be used in TMA construction. Prior knowledge of tissue thickness in TMA construction can prompt compensatory steps that can enhance the yield of valuable samples and assure sufficient numbers of adequate cores for statistical analysis in biomarker evaluations

OBJECTIVES: We have previously reported on the disparity in the clinicopathologic features of prostate cancer between black and white patients at our equal-access institution during the 1990s. The goal of this study was to determine whether the worse clinicopathologic features of prostate cancer in black patients have persisted in the 2000s. METHODS: We examined 362 men (224 black and 138 white) treated with radical prostatectomy at the Veterans Affairs Medical Center in New York. We compared the clinicopathologic variables between 227 patients treated during the 1990s (group 1) and 135 treated in the 2000s (group 2). RESULTS: In group 1, black patients were significantly younger (P < 0.001) and had a greater prostate-specific antigen (PSA) level (P = 0.001), Gleason score (P = 0.005), and stage (P = 0.03) than white patients. In group 2, black patients continued to have significantly greater PSA levels (P = 0.04) and Gleason scores (P = 0.005) than white patients. Comparing only the black patients, those in group 2 had significantly lower PSA levels (P < 0.001) and stage (P = 0.03), but had worse Gleason scores (P = 0.03) than those in group 1. On multivariate analysis, black patients were significantly more likely to have a worse Gleason score (P = 0.005) than white patients. CONCLUSIONS: Our data have demonstrated a narrowing of the differences in pathologic stage between black and white patients in the 2000s. However, black men have continued to have worse Gleason scores and greater PSA levels than white patients. These findings suggest that there may be different patterns of molecular alterations in black men that may contribute to the poor tumor differentiation. Additional research is underway to better characterize these underlying molecular mechanisms

Androgen receptor (AR) is a ligand-activated transcription factor that mediates the action of androgens and is essential for the growth, function, and cell differentiation of the prostate gland. Here, we demonstrated that the prostate apoptosis response factor-4 (par-4) functions as a novel AR coactivator. Par-4 physically interacted with the DNA-binding domain of AR, enhanced AR interaction with DNA, and increased AR-dependent transcription. Par-4 enhanced the c-FLIP promoter activity and was recruited on to the c-FLIP gene in the presence of androgens, and the dominant-negative par-4 decreased c-FLIP expression. These results suggest that, in addition to its proapoptotic function, par-4 acts as a novel transcription cofactor for AR to target c-FLIP gene expression. In addition, we demonstrated that loss of c-FLIP expression was essential for castration-induced apoptosis in the prostate gland and that enhanced c-FLIP expression was associated with prostate cancer progression to the androgen-resistant stage. Our data shed light on a transcription-mediated mechanism for the effects of the AR pathway on cell survival and apoptosis

We recently demonstrated that EGFR protein overexpression is more common in African American (AA) prostate cancer patients compared to Caucasian patients. We further examine EGFR dysregulation by determining EGFR mutation status in the tyrosine kinase (TK) domain in prostate cancer patients of different ethnicity. Normal and tumor DNA from 89 radical prostatectomy cases were studied for mutations in the EGFR TK domain using genomic DNA sequencing. We identified 4 novel missense mutations in exons 19, 20 and 21 of EGFR TK domain: 3 in Koreans and 1 in Caucasian but none in AA. We also identified 5 distinct synonymous DNA sequence changes, which did not alter the encoded amino acid, in exons 20 and 21 in 31/89 (35%) patients. Interestingly, these synonymous sequence changes were not observed in normal DNA in 7(23%) patients, indicating the presence of de novo somatic mutation to a new synonymous sequence. Our data reveal that EGFR missense mutation in the TK domain occurs in localized prostate cancer. Our data also demonstrate the presence of somatic mutation to a new synonymous sequence in a subset of patients. Larger population-based studies are required to define the association between EGFR mutations and the ethnic background of patients

SUMO is a novel ubiquitin-like protein that can covalently modify a large number of nuclear proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. Sumoylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and is readily reversed by a family of SUMO-specific proteases (SENPs). Since SUMO was discovered 10 years ago, the biologic contribution of this posttranslational modification has remained unclear. In this review, we report that SENP1, a member of the SENP family, is overexpressed in human prostate cancer specimens. The induction of SENP1 is observed with the chronic exposure of prostate cancer cells to androgen and/or interleukin (IL) 6. SENP1 upregulation modulates the transcriptional activity of androgen receptors (ARs) and c-Jun, as well as cyclin D1 expression. Initial in vivo data from transgenic mice indicate that overexpression of SENP1 in the prostate leads to the development of prostatic intraepithelial neoplasia at an early age. Collectively, these studies indicate that overexpression of SENP1 is associated with prostate cancer development

Various cofactors have been shown to regulate androgen receptor (AR) transactivation, but their physiological functions in the AR pathway and prostate tumorigenesis are undefined. Here, we found that AR cofactor (p44) translocation from the nucleus to the cytoplasm in prostate epithelial cells (ECs) is associated with prostate tumorigenesis. The forced nuclear localization of p44 inhibited prostate cancer cell growth by G1 cell-cycle arrest. Consistently, mice lacking one allele of the p44 gene developed prostatic hyperplasia. Therefore, p44 is required for proper expression of AR-target genes to maintain the differentiation of prostate ECs, and p44 translocation from the nucleus into the cytoplasm in prostate cancer cells or loss of one allele in mouse results in excessive prostate EC proliferation