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

Luciana Schultz, Roula Albadine, Jessica Hicks, Sana Jadallah, Angelo M. Demarzo, Ying Bei Chen, Matthew E. Neilsen, Mark L. Gonzalgo, David Sidransky, Mark Schoenberg, George J. Netto

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5517-5526
Number of pages10
JournalCancer
Volume116
Issue number23
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Keywords

  • 4E-BP1
  • Akt
  • Pten
  • bladder
  • c-myc
  • mammalian target of rapamycin
  • p27
  • phosS6
  • urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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