title: Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer.
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.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM:600, Room N1110, Houston, TX 77030, USA.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Migliaccio
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutierrez
authors.forename: Luca
authors.initials: L
authors.lastname: Malorni
authors.forename: Syed K
authors.initials: SK
authors.lastname: Mohsin
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Heidi
authors.initials: H
authors.lastname: Weiss
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002467:Cell Nucleus / Q000737:chemistry*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000032:analysis*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen