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

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.

[1]  S. Andò,et al.  The estrogen receptor α:insulin receptor substrate 1 complex in breast cancer: structure–function relationships , 2007 .

[2]  E. Wickstrom,et al.  RNAi‐mediated silencing of insulin receptor substrate 1 (IRS‐1) enhances tamoxifen‐induced cell death in MCF‐7 breast cancer cells , 2006, Journal of cellular biochemistry.

[3]  D. Allred,et al.  Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study , 2004, Modern Pathology.

[4]  A. Benner,et al.  Down‐regulation of insulin‐like growth factor‐I receptor and insulin receptor substrate‐1 expression in advanced human breast cancer , 2000, International journal of cancer.

[5]  E. Surmacz.  Function of the IGF-I Receptor in Breast Cancer , 2004, Journal of Mammary Gland Biology and Neoplasia.

[6]  S. Andò,et al.  Expression of nuclear insulin receptor substrate 1 in breast cancer , 2006, Journal of Clinical Pathology.

[7]  Leslie M. Shaw,et al.  Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis , 2006, Molecular and Cellular Biology.

[8]  M. Sułkowska,et al.  Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases , 2005, Journal of Clinical Pathology.

[9]  S. Andò,et al.  Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells , 1999, International journal of cancer.

[10]  W. McGuire,et al.  Immunohistochemistry on Histological Sections from Small (50 mg) Samples of Pulverized Breast Cancer , 1993 .

[11]  Adrian V. Lee,et al.  Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  E. Surmacz,et al.  Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. , 2003, Oncogene.

[13]  E. Surmacz,et al.  Overexpression of insulin receptor substrate 1 (IRS-1) in the human breast cancer cell line MCF-7 induces loss of estrogen requirements for growth and transformation. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  F. May,et al.  Insulin Receptor Substrate-1 Expression Is Regulated by Estrogen in the MCF-7 Human Breast Cancer Cell Line* , 2000, The Journal of Biological Chemistry.

[15]  S. Andò,et al.  Estradiol increases IRS-1 gene expression and insulin signaling in breast cancer cells. , 2001, Biochemical and biophysical research communications.

[16]  D. Yee,et al.  Insulin Receptor Substrate-1 is the Predominant Signaling Molecule Activated by Insulin-like Growth Factor-I, Insulin, and Interleukin-4 in Estrogen Receptor-positive Human Breast Cancer Cells* , 1998, The Journal of Biological Chemistry.

[17]  Adrian V. Lee,et al.  Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. , 2005, Journal of the National Cancer Institute.

[18]  C K Osborne,et al.  Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  E. Surmacz,et al.  Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells. , 1997, Experimental cell research.

[20]  D. Allred,et al.  Prognostic and predictive factors in breast cancer by immunohistochemical analysis. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[21]  Adrian V. Lee,et al.  Oncogenic Transformation by the Signaling Adaptor Proteins Insulin Receptor Substrate (IRS)-1 and IRS-2 , 2007, Cell cycle.

[22]  C. Osborne,et al.  Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  S. Andò,et al.  The estrogen receptor alpha:insulin receptor substrate 1 complex in breast cancer: structure-function relationships. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  C. Osborne,et al.  Tamoxifen in the treatment of breast cancer. , 1998, The New England journal of medicine.

[25]  A. Vecchione,et al.  Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters , 2004, Oncogene.

[26]  S. Hilsenbeck,et al.  Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. , 1999, Molecular endocrinology.

[27]  E. Surmacz,et al.  Estrogen receptor-α regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells , 2003, Oncogene.

[28]  C. Kahn,et al.  Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland. , 2003, Endocrinology.

[29]  R. Nicholson,et al.  Insulin receptor substrate-1 involvement in epidermal growth factor receptor and insulin-like growth factor receptor signalling: implication for Gefitinib (‘Iressa’) response and resistance , 2008, Breast Cancer Research and Treatment.

[30]  J. Chen,et al.  Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes , 2008, Oncogene.

[31]  S. Hilsenbeck,et al.  Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  A. Vecchione,et al.  Nuclear insulin receptor substrate 1 interacts with estrogen receptor alpha at ERE promoters. , 2004, Oncogene.

[33]  I. Casaburi,et al.  Nuclear Translocation of Insulin Receptor Substrate-1 by Oncogenes And Igf-I , 2002, The Journal of Biological Chemistry.

[34]  Osborne Ck,et al.  Tamoxifen in the Treatment of Breast Cancer , 1998 .

[35]  M. Prisco,et al.  Differential roles of IRS‐1 and SHC signaling pathways in breast cancer cells , 1997, International journal of cancer.