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 Mills, Ana M. Gonzalez-Angulo

Research output: Contribution to journalArticle

42 Citations (Scopus)

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
Externally publishedYes

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S 6
Apoptosis Regulatory Proteins
Hormones
Breast Neoplasms
Eukaryotic Initiation Factor-4E
Survival
Elongation Factor 2 Kinase
Peptide Elongation Factor 2
Proteins
Recurrence
Phosphotransferases
Ribosomal Protein S6
Protein Array Analysis
Neoplasms
Carrier Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Meric-Bernstam, F., Chen, H., Akcakanat, A., Do, K. A., Lluch, A., Hennessy, B. T., ... 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

Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. / Meric-Bernstam, Funda; Chen, Huiqin; Akcakanat, Argun; Do, Kim Anh; Lluch, Ana; Hennessy, Bryan T.; Hortobagyi, Gabriel N.; Mills, Gordon; Gonzalez-Angulo, Ana M.

In: Breast Cancer Research, Vol. 14, No. 5, R138, 26.10.2012.

Research output: Contribution to journalArticle

Meric-Bernstam, F, Chen, H, Akcakanat, A, Do, KA, Lluch, A, Hennessy, BT, Hortobagyi, GN, Mills, G & Gonzalez-Angulo, AM 2012, 'Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer', Breast Cancer Research, vol. 14, no. 5, R138. https://doi.org/10.1186/bcr3343
Meric-Bernstam, Funda ; Chen, Huiqin ; Akcakanat, Argun ; Do, Kim Anh ; Lluch, Ana ; Hennessy, Bryan T. ; Hortobagyi, Gabriel N. ; Mills, Gordon ; Gonzalez-Angulo, Ana M. / Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. In: Breast Cancer Research. 2012 ; Vol. 14, No. 5.
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title = "Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer",
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.",
author = "Funda Meric-Bernstam and Huiqin Chen and Argun Akcakanat and Do, {Kim Anh} and Ana Lluch and Hennessy, {Bryan T.} and Hortobagyi, {Gabriel N.} and Gordon Mills and Gonzalez-Angulo, {Ana M.}",
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T1 - Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer

AU - Meric-Bernstam, Funda

AU - Chen, Huiqin

AU - Akcakanat, Argun

AU - Do, Kim Anh

AU - Lluch, Ana

AU - Hennessy, Bryan T.

AU - Hortobagyi, Gabriel N.

AU - Mills, Gordon

AU - Gonzalez-Angulo, Ana M.

PY - 2012/10/26

Y1 - 2012/10/26

N2 - 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.

AB - 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.

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