Breast Cancer Research and Treatment

, Volume 123, Issue 3, pp 651–660

Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer

  • Ilenia Migliaccio
  • Meng-Fen Wu
  • Carolina Gutierrez
  • Luca Malorni
  • Syed K. Mohsin
  • D. Craig Allred
  • Susan G. Hilsenbeck
  • C. Kent Osborne
  • Heidi Weiss
  • Adrian V. Lee
Preclinical study

DOI: 10.1007/s10549-009-0632-6

Cite this article as:
Migliaccio, I., Wu, MF., Gutierrez, C. et al. Breast Cancer Res Treat (2010) 123: 651. doi:10.1007/s10549-009-0632-6

Abstract

Insulin receptor substrate-1 (IRS-1) is a cytoplasmic scaffolding protein that is phosphorylated by insulin-like growth factor-I receptor and recruits downstream effectors. Recent evidence suggests that IRS-1 has a nuclear localization and function. Here we investigated whether nuclear and cytoplasmic IRS-1 levels are associated with clinico-pathological characteristics and clinical outcome in breast cancer patients. Tissue microarrays from 1,097 patients with stage I–II breast cancer were stained by immunohistochemistry for IRS-1. Nuclear and cytoplasmic IRS-1 were scored separately according to the Allred score. Nuclear IRS-1 showed a positive association with estrogen receptor (ER) (r = 0.09, P = 0.003) and progesterone receptor (PR) (r = 0.08, P = 0.008) status and a negative correlation with lymph node involvement (r = −0.10, P = 0.001). Cytoplasmic IRS-1 did not correlate with ER or PR but showed a positive correlation with tumor size (r = 0.10, P = 0.001) and S-phase fraction (r = 0.16, P < 0.001). In univariate analysis, tamoxifen-treated patients with tumors showing positive nuclear IRS-1 had a better recurrence-free survival (RFS) (P = 0.009) and overall survival (OS) (P = 0.0007), while no association was shown between cytoplasmic IRS-1 and RFS or OS in the same group of patients. In multivariate analysis of patients receiving tamoxifen, negative nuclear IRS-1 showed a significantly reduced RFS (P = 0.046) and OS (P = 0.018). Combining both PR and nuclear IRS-1, tamoxifen-treated patients with PR+/IRS-1+ tumors had a better RFS (P = 0.0003) and OS (P < 0.0001) when compared with patients with PR−/IRS-1− tumors. In conclusion, nuclear IRS-1 may be a useful marker to predict tamoxifen response in patients with early breast cancer, particularly when assessed in combination with PR.

Keywords

IRS1IRS-1Breast cancerPrognosisEstrogen receptor

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Ilenia Migliaccio
    • 1
    • 2
  • Meng-Fen Wu
    • 3
  • Carolina Gutierrez
    • 5
  • Luca Malorni
    • 1
    • 6
  • Syed K. Mohsin
    • 7
  • D. Craig Allred
    • 8
  • Susan G. Hilsenbeck
    • 1
    • 3
  • C. Kent Osborne
    • 1
    • 3
  • Heidi Weiss
    • 9
  • Adrian V. Lee
    • 1
    • 4
  1. 1.Lester and Sue Smith Breast CenterBaylor College of MedicineHoustonUSA
  2. 2.Dipartimento di Scienze Biomorfologiche e FunzionaliUniversitá degli Studi di Napoli, “Federico II”NapoliItaly
  3. 3.Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  4. 4.Department of Medicine and Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA
  5. 5.Department of PathologyBaylor College of MedicineHoustonUSA
  6. 6.Dipartimento di Endocrinologia e Oncologia Molecolare e ClinicaUniversitá degli Studi di Napoli, “Federico II”NapoliItaly
  7. 7.Department of PathologyRiverside Methodist HospitalColumbusUSA
  8. 8.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  9. 9.Department of Preventive Medicine and Community Health, Sealy Center for Cancer Cell BiologyUniversity of Texas Medical BranchGalvestonUSA