NOXA and PUMA Expression Add to Clinical Markers in Predicting Biochemical Recurrence of Prostate Cancer Patients in a Survival Tree Model

Abstract

Purpose: To assess the expression of proapoptotic NOXA and PUMA in prostate tissues and delineate their association with prostate cancer (PCa) recurrence. Experimental Design: Normal, prostatic intraepithelial neoplasia (PIN), hormone-sensitive (HS) PCa, and hormone-refractory (HR) PCa tissues were used to build tissue microarrays encompassing a total of 135 patients. Two observers assessed the intensity of NOXA and PUMA immunohistochemical staining using a composite color scale. One hundred and eighty recursive partitioning and regression tree (RPART) models were generated to predict biochemical recurrence (BCR) within HS cancer patients using NOXA, PUMA, and clinical parameters. Models were then ranked according to the integrated Brier score (IBS). Results: Increasing NOXA expression was associated with PCa progression, reaching the highest levels in HRPCa. Increased NOXA expression was observed in 68% of HS cancer patients and was predictive of BCR (LR = 8.64; P = 0.003). In contrast, PUMA expression was highest in HS cancer, and although 70% of HS cancer patients exhibited increased PUMA expression, PUMA alone could not predict the onset of BCR. Interestingly, the top-ranking RPART model generated [IBS = 0.107; 95% confidence interval (95% CI), 0.065-0.128] included surgical margin status and NOXA and PUMA expression, although recurrent prognostic classification schemes obtained in the top10 models favored a survival tree model containing margin status, NOXA expression, and preoperative prostate-specific antigen (PSA) (IBS = 0.114; 95% CI, 0.069-0.142). Conclusion: We conclude that NOXA and PUMA expression may be linked to PCa progression and propose further validation of a survival tree model including surgical margin status, NOXA expression, and preoperative PSA for predicting BCR.

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

“…Next, we investigated the correlation between eIF4E phosphorylation in human prostate cancer and disease progression. A tissue microarray (TMA) constructed with human prostate cancer (PCa) samples including patients presenting primary and hormone-refractory PCa (HR PCa) was used (31,32). Both eIF4E and phospho-eIF4E staining intensity in- creased gradually from normal to PIN, to hormone-sensitive (HS), and further to HR PCa tumors (Fig.…”

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

“…Notable genes elevated in the AR-E231G model included Rb1 32 and Ccr2, 33 both of which have been shown to be overexpressed in clinical prostate cancer, and Pmaip1, a gene that is predictive of BCR in human disease. 34 Expression of the tumor suppressor genes Vangl2, Apc and Abi1 35,36 was reduced in AR-E231G samples. Ten of the 13 members of the androgen-responsive and mouse-specific kallikrein Klk1b family were increased in AR-E231G prostates, suggesting that these factors could be a useful marker of prostate cancer initiation in mouse models.…”

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

“…We used samples from seven patients diagnosed with BPH and five different tissue microarrays (TMAs) (Diallo et al 2007). The first is comprised of 49 normal prostate specimens from autopsies.…”

“…They are comprised of related nonneoplasic tissues adjacent to prostate cancer and cancerous tissues from 64 patients who underwent radical prostatectomy. Regions of normal, intraepithelial neoplasia or cancerous epithelial tissue were identified by two pathologists and subsequently spotted on TMAs (Diallo et al 2007). Specimens were obtained from consenting patients, and the institutional ethics review committee approved the study.…”