Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer

Funda Meric-Bernstam, Huiqin Chen, Argun Akcakanat, Kim Anh Do, Ana Lluch, Bryan T. Hennessy, Gabriel N. Hortobagyi, Gordon B. Mills, Ana M. Gonzalez-Angulo

    Research output: Contribution to journalArticle

    44 Scopus citations

    Abstract

    Introduction: Translation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and phosphorylated ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Further, translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). We sought to determine the association of these translational aberrations with clinical-pathologic factors and survival outcomes in hormone receptor-positive breast cancer.Methods: Primary tumors were collected from 190 patients with Stage I to III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays. Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed.Results: High eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node positivity. Median follow-up for living patients was 96 months.High p4E-BP1 T36/47, p4E-BP1 S65, p4E-BP1 T70 and 4E-BP1 were associated with worse RFS. High p4E-BP1 T70 and pS6 S235/236, and low pdcd4, were associated with worse OS. In multivariable analysis, in addition to positive nodes, p4E-BP1 S65 remained a significant predictor of RFS (HR = 1.62, 95% CI = 1.13-2.31; P = 0.008). In addition to age, pS6 S235/236 (HR = 1.73, 95% CI = 1.03-2.90, P = 0.039), eEF2K (HR = 2.19, 95% CI = 1.35-3.56, P = 0.002) and pdcd4 (HR = 0.42, 95% CI = 0.25-0.70, P = 0.001) were associated with OS.Conclusions: Increased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer, suggesting their role as prognostic markers and therapeutic targets.

    Original languageEnglish (US)
    Article numberR138
    JournalBreast Cancer Research
    Volume14
    Issue number5
    DOIs
    StatePublished - Oct 26 2012

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Fingerprint Dive into the research topics of 'Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Meric-Bernstam, F., Chen, H., Akcakanat, A., Do, K. A., Lluch, A., Hennessy, B. T., Hortobagyi, G. N., Mills, G. B., & Gonzalez-Angulo, A. M. (2012). Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. Breast Cancer Research, 14(5), [R138]. https://doi.org/10.1186/bcr3343