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

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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.

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Acknowledgments

This project was supported in part by funding from Susan G Komen for the Cure (A.V.L.), and supported by NIH P50CA58183 (C.K.O) from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Susan G. Komen for the Cure, the National Cancer Institute, or the National Institutes of Health.

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Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM:600, Room N1110, Houston, TX, 77030, USA

    Ilenia Migliaccio, Luca Malorni, Susan G. Hilsenbeck, C. Kent Osborne & Adrian V. Lee

  2. Dipartimento di Scienze Biomorfologiche e Funzionali, Universitá degli Studi di Napoli, “Federico II”, 80131, Napoli, Italy

    Ilenia Migliaccio

  3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Meng-Fen Wu, Susan G. Hilsenbeck & C. Kent Osborne

  4. Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Adrian V. Lee

  5. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    Carolina Gutierrez

  6. Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universitá degli Studi di Napoli, “Federico II”, 80131, Napoli, Italy

    Luca Malorni

  7. Department of Pathology, Riverside Methodist Hospital, Columbus, OH, USA

    Syed K. Mohsin

  8. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    D. Craig Allred

  9. Department of Preventive Medicine and Community Health, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX, USA

    Heidi Weiss

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  1. Ilenia Migliaccio
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  2. Meng-Fen Wu
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  3. Carolina Gutierrez
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  4. Luca Malorni
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  5. Syed K. Mohsin
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  6. D. Craig Allred
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  7. Susan G. Hilsenbeck
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  8. C. Kent Osborne
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  9. Heidi Weiss
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  10. Adrian V. Lee
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Correspondence to Adrian V. Lee.

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Migliaccio, I., Wu, MF., Gutierrez, C. et al. Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer. Breast Cancer Res Treat 123, 651–660 (2010). https://doi.org/10.1007/s10549-009-0632-6

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  • DOI: https://doi.org/10.1007/s10549-009-0632-6

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