title: Phosphorylated 4E-BP1 is associated with poor survival in melanoma.
abstract: OBJECTIVE
  Both phosphatidylinositol 3-kinase/AKT and RAS/mitogen-activated protein kinase signal transduction pathways mediate 4E-BP1 phosphorylation, releasing 4E-BP1 from the mRNA cap and permitting translation initiation. Given the prevalence of PTEN and BRAF mutations in melanoma, we first examined translation initiation, as measured by phosphorylated 4E-BP1 (p-4E-BP1), in metastatic melanoma tissues and cell lines. We then tested the association between amounts of total and p-4E-BP1 and patient survival.
  
  
  METHODS
  Seven human metastatic melanoma cells lines and 72 metastatic melanoma patients with accessible metastatic tumor tissues and extended follow-up information were studied. Expression of 4E-BP1 transcript, total 4E-BP1 protein, and p-4E-BP1 was examined. The relationship between 4E-BP1 transcript and protein expression was assessed in a subset of patient tumors (n = 41). The association between total and p-4E-BP1 levels and survival was examined in the larger cohort of patients (n = 72).
  
  
  RESULTS
  4E-BP1 was hyperphosphorylated in 4 of 7 melanoma cell lines harboring both BRAF and PTEN mutations compared with untransformed melanocytes or RAS/RAF/PTEN wild-type melanoma cells. 4E-BP1 transcript correlated with 4E-BP1 total protein levels as measured by the semiquantitative reverse-phase protein array (P = 0.012). High levels of p-4E-BP1 were associated with worse overall and post-recurrence survival (P = 0.02 and 0.0003, respectively).
  
  
  CONCLUSIONS
  Our data show that translation initiation is a common event in human metastatic melanoma and correlates with worse prognosis. Therefore, effective inhibition of the pathways responsible for 4E-BP1 phosphorylation should be considered to improve the treatment outcome of metastatic melanoma patients.
authors.affiliation: Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: O'Reilly
authors.forename: Melanie
authors.initials: M
authors.lastname: Warycha
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rodrik
authors.forename: Xi K
authors.initials: XK
authors.lastname: Zhou
authors.forename: Herman
authors.initials: H
authors.lastname: Yee
authors.forename: David
authors.initials: D
authors.lastname: Polsky
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Gordon
authors.initials: G
authors.lastname: Mills
authors.forename: Iman
authors.initials: I
authors.lastname: Osman