The quality of the older tissue samples may not be the same as the newer tissue samples, which may affect, to some degree, the fidelity this quantitative study intended to accomplish

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The quality of the older tissue samples may not be the same as the newer tissue samples, which may affect, to some degree, the fidelity this quantitative study intended to accomplish. In summary, our findings confirm that TMPRSS2-ERG fusion is AR-dependent and is associated with increased AR expression. visualized with a different chromogen. We found marked difference in AR expression levels between ERG positive (ERG+) and ERG unfavorable (ERG-) prostate cancer. The difference was significant in localized (pT2) prostate cancer. We also found that AR expression levels were significantly higher in PCa tissue compared to benign prostate tissue, with the highest expression levels in ERG+ metastatic cancer. Neither AR nor ERG expression was associated with clinical outcome. Our findings confirm that TMPRSS2-ERG fusion is usually AR-dependent and is associated with increased AR expression. Our data suggest that the AR pathway may play an important role in the development of ERG+ PCa and ERG status may be useful in stratifying PCa patients for hormonal therapy. 0.01 compared to Benign Prostate; Core #: number of cores analyzed; OD: optical density; SD: standard deviation. ERG status (TMPRSS2-ERG fusion) of the PCa patients in the two cohorts Similar to most published studies, we found 49% of PCa samples express ERG (ERG+) in cohort 1, and 53% of PCa samples are ERG+ in cohort 2. AR expression levels in ERG+ and ERG- PCa samples When further stratifying patients in both cohorts according to ERG status (ERG+ vs. ERG-) we found that AR expression levels in ERG+ PCa overall are much higher than those in ERG- PCa and the difference is usually statistically significant only in localized PCa group in cohort 1 and in no-recurrence PCa group in cohort 2 (p 0.01; Physique 3A and ?and3B,3B, Table 4). Open in a separate window Physique 3 Nuclear AR expression levels of the prostate tissue samples from the two PCa cohorts. AR expression levels in ERG+ PCa overall are much higher than those in ERG- PCa and the difference is usually statistically significant only in localized PCa group in cohort 1 (A) and in no-recurrence PCa group in cohort 2 (B) (p 0.01). Table 4 Nuclear AR Expression in Prostate Cancer Stratified by ERG Status 0.001 ERG+ vs. ERG-; ERG+ PCa = 51% in pTMA cohort, ERG+ PCa = 42% in oTMA cohort. Discussion To the best of our knowledge, we believe this is the first quantitative study on AR expression in PCa with different ERG status using multiplexed IHC and multispectral imaging technology and two dense TMA samples. This quantitative approach allows us to study ERG and AR simultaneously on a single TMA section. It removes subjectivity and allows precise quantitation of target proteins either constantly (mean OD/pixel) or categorically (positive vs. unfavorable). Our data obtained from the two cohorts are concordant with each other and confirm the previous report by Minner and colleagues that there is a marked difference in AR expression levels between ERG+ and ERG- PCa [28]. Elevated expression of AR in ERG+ VGX-1027 PCa, then, suggests a dosage effect of AR in the expression of TMPRSS2-ERG fusion. Mani and colleagues reported that androgen signaling induces spatial proximity of TMPRSS2 and ERG genomic loci, both located on chromosome 21q22, VGX-1027 and facilitates the formation of the TMPRSS2 and ERG fusion in LNCaP cells [27]. Bastus and colleaguse reported that treatment with androgen can induce the TMPRSS2-ERG fusion in both malignant and nonmalignant prostate epithelial cells. Although the fusion could be detected in malignant cells following 24-hour treatment, prolonged exposure to androgen was required to detect the fusion transcript in nonmalignant Rabbit Polyclonal to EPHA7 (phospho-Tyr791) cells. Their data suggested that androgen-induced gene proximity, androgen receptor exon1 CAG repeat length and expression of the VGX-1027 PIWIL1 gene were the driving factors. Their VGX-1027 experiments exhibited that fusions can be induced prior to malignant transformation and generation of the fusion is usually associated with both gene proximity and loss of the ability to prevent double-strand breaks [30]. Other studies also provided evidences that AR and ERG are closely linked in the development of PCa [31-33]. Our finding further supports that AR signaling plays a key role in the formation of TMPRSS2-ERG fusion. With those data in mind, one might inquire: Can ERG status determine and predict cancer patients responsiveness to androgen deprivation therapy (ADT) or chemoradiation therapy? Can we use ERG status to subtype PCa and to select potentially effective therapy for the patients? Karnes and colleagues reported that the ability of DNA isotopomerase 2 (TOP2a) and MIB-1 to predict systemic progression in men with high-risk PCa is dependent on ERG status. They also found that the response to adjuvant ADT therapy.