A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma

• Published in: BJU international 2012-12, Vol.110 (11c), p.E1237-E1248
• Main Authors: Korkolopoulou, Penelope, Levidou, Georgia, Trigka, Eleni‐Andriana, Prekete, Niki, Karlou, Maria, Thymara, Irene, Sakellariou, Stratigoula, Fragkou, Paraskevi, Isaiadis, Dimitrios, Pavlopoulos, Petros, Patsouris, Efstratios, Saetta, Angelica A.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 4E‐BP1; Adult; Aged; Aged, 80 and over; AKT; AKT protein; AKT1; AKT1 protein; bladder cancer; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Carcinoma, Transitional Cell - pathology; Chemotherapy; Class I Phosphatidylinositol 3-Kinases; DNA, Neoplasm - genetics; Extracellular signal-regulated kinase; Female; Fibroblast growth factor receptor 3; Fibroblast growth factor receptors; Follow-Up Studies; Humans; Immunohistochemistry; Initiation factors; Kinases; Male; Middle Aged; mTOR; Mutation; Oncogenes; p70S6K; p85aPI3K; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; phosphoinositides; PIK3CA; Polymerase Chain Reaction; Prognosis; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Regulatory subunits; Retrospective Studies; Signal Transduction; Studies; Survival; Survival analysis; thymoma; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumorigenesis; UCS; Urinary bladder; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; urothelial carcinoma; urothelium
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/j.1464-410X.2012.11569.x

What's known on the subject? and What does the study add? A few published studies investigating single or various PI3K/AKT/mTOR signalling components have produced inconsistent results. Moreover, PI3K regulatory subunit p85a and activated p70S6K expression levels have not been previously examined in urothelial carcinoma (UC). The present study addresses simultaneously all key members of PI3K/AKT/mTOR signalling cascade supporting a differential implication of PI3K/AKT/mTOR pathway components in urothelial tumorigenesis. Furthermore, we propose p‐4E‐BP1 as a potential prognostic marker in UC, which might assist the selection of patients more likely to benefit from chemotherapy regimens based on PI3K/AKT/mTOR pathway inhibition. Finally, the present study indicates PIK3CA/AKT1 mutational status as a potential predictive marker for time‐to‐recurrence. OBJECTIVE •  To perform a comprehensive simultaneous assessment of all key members of phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway along with AKT homolog 1 (AKT1) and PIK3 catalytic alpha polypeptide (PIK3CA) mutations in bladder urothelial carcinoma (UC). •  Published information is limited to a few studies looking into single or various combinations of members of this pathway with inconsistent results. In particular the expression status of phosphorylated (p‐)p70S6 kinase (p70S6K) and p85a subunit of PI3K has not been tested in UC. PATIENTS AND METHODS •  Paraffin‐embedded transurethral resection tissue from 113 patients with UC was investigated for the association of p85aPI3K, p‐AKT, p‐mTOR, p‐p70S6K and p‐4E‐BP1 (eukaryotic initiation factor 4E‐binding protein 1) expression status, as well as PIK3CA and AKT1 mutations with p‐extracellular signal‐regulated kinase 1/2 (ERK1/2), fibroblast growth factor receptor 3 (FGFR3), pathological features, recurrence and cancer‐specific survival. RESULTS •  With the exception of p‐p70S6K, all others components of the PI3K/AKT/mTOR pathway were upregulated in UCs as compared with normal urothelium. •  p‐mTOR expression strongly correlated with its upstream p‐AKT and marginally with its downstream p‐p70S6K. p85aPI3K and p‐ERK1/2 levels were also marginally correlated. •  PIK3CA and AKT1 mutations were distinctly uncommon and mutually exclusive, without any association with pathological features. However, the presence of AKT1 mutations was associated with increased FGFR3 levels and was restricted to p85aP