Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy

• Published in: Cancer Vol. 116; no. 23; pp. 5517 - 5526
• Main Authors: Schultz, Luciana, Albadine, Roula, Hicks, Jessica, Jadallah, Sana, DeMarzo, Angelo M., Chen, Ying‐Bei, Neilsen, Matthew E., Gonzalgo, Mark L., Sidransky, David, Schoenberg, Mark, Netto, George J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2010; Wiley-Blackwell
• Subjects: 4E‐BP1; Aged; Akt; Biological and medical sciences; Biomarkers, Tumor - metabolism; bladder; Cancer; Cystectomy; c‐myc; Female; Histology; Humans; lymph nodes; Male; mammalian target of rapamycin; Medical sciences; Middle Aged; migration; Morbidity; Mortality; Nephrology. Urinary tract diseases; p27; phosS6; Prognosis; Pten; Signal Transduction; survival; Tissue Array Analysis; TOR Serine-Threonine Kinases - metabolism; Tumors; Tumors of the urinary system; urinary bladder; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - surgery; Urinary tract. Prostate gland; urothelial carcinoma; Urothelium; KIP1 Gene; Prognosis; c-myc; Transitional cell carcinoma; Cancerology; phosS6; Urinary bladder; Surgery; PTEN Gene; Protooncogene; Tumor suppressor gene; Urinary system disease; Akt protein kinase; Urinary tract disease; Malignant tumor; Akt; Pten; Baldder transitional cell carcinoma; Cystectomy; Treatment; urothelial carcinoma; Urinary system; p27; C-Onc gene; Mammalian target of rapamycin; bladder; myc Gene; Bladder disease; 4E-BP1; Cancer
• DOI: 10.1002/cncr.25502
• ISSN: 0008-543X; 1097-0142

BACKGROUND: Bladder urothelial carcinoma has high rates of mortality and morbidity. Identifying novel molecular prognostic factors and targets of therapy is crucial. Mammalian target of rapamycin (mTOR) pathway plays a pivotal role in establishing cell shape, migration, and proliferation. METHODS: Tissue microarrays were constructed from 132 cystectomies (1994‐2002). Immunohistochemistry was performed for Pten, c‐myc, p27, phosphorylated (phos)Akt, phosS6, and 4E‐BP1. Markers were evaluated for pattern, percentage, and intensity of staining. RESULTS: Mean length of follow‐up was 62.6 months (range, 1‐182 months). Disease progression, overall survival (OS), and disease‐specific survival (DSS) rates were 42%, 60%, and 68%, respectively. Pten showed loss of expression in 35% of bladder urothelial carcinoma. All markers showed lower expression in invasive bladder urothelial carcinoma compared with benign urothelium with the exception of 4E‐BP1. Pten, p27, phosAkt, phosS6, and 4E‐BP1 expression correlated with pathologic stage (pathological stage; P<.03). Pten, 4E‐BP1, and phosAkt expression correlated with divergent aggressive histology and invasion. phosS6 expression inversely predicted OS (P = .01), DSS (P = .001), and progression (P = .05). c‐myc expression inversely predicted progression (P = .01). In a multivariate analysis model that included TNM stage grouping, divergent aggressive histology, concomitant carcinoma in situ, phosS6, and c‐myc expression, phosS6 was an independent predictor of DSS (P = .03; hazard ratio [HR], −0.19), whereas c‐myc was an independent predictor of progression (P = .02; HR, −0.38). In a second model substituting organ‐confined disease and lymph node status for TNM stage grouping, phosS6 and c‐myc remained independent predictors of DSS (P = .03; HR, −0.21) and progression (P = .03; HR, −0.34), respectively. CONCLUSIONS: We found an overall down‐regulation of mTOR pathway in bladder urothelial carcinoma. phosS6 independently predicted DSS, and c‐myc independently predicted progression. Cancer 2010. © 2010 American Cancer Society. Mammalian target of rapamycin pathway was overall down‐regulated in urothelial carcinoma. Phosphorylated S6 protein was an independent predictor of disease‐specific survival, and c‐myc was an independent predictor of progression.