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. 2011 Dec;130(3):759-72.
doi: 10.1007/s10549-011-1353-1. Epub 2011 Jan 22.

Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer

Jennifer L Clark  1 , Karen Dresser, Chung-Cheng Hsieh, Michael Sabel, Celina G Kleer, Ashraf Khan, Leslie M Shaw
Affiliations

Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer

Jennifer L Clark et al. Breast Cancer Res Treat. 2011 Dec.

Abstract

Recent studies have identified a role for insulin receptor substrate-2 (IRS-2) in promoting motility and metastasis in breast cancer. However, no published studies to date have examined IRS-2 expression in human breast tumors. We examined IRS-2 expression by immunohistochemistry (IHC) in normal breast tissue, benign breast lesions, and malignant breast tumors from the institutional pathology archives and a tumor microarray from a separate institution. Three distinct IRS-2 staining patterns were noted: diffusely cytoplasmic, punctate cytoplasmic, and localized to the cell membrane. The individual and pooled datasets were analyzed for associations of IRS-2 staining pattern with core clinical parameters and clinical outcomes. Univariate analysis revealed a trend toward decreased overall survival (OS) with IRS-2 membrane staining, and this association became significant upon multivariate analysis (P = 0.01). In progesterone receptor negative (PR-) tumors, in particular, IRS-2 staining at the membrane correlated with significantly worse OS than other IRS-2 staining patterns (P < 0.001). When PR status and IRS-2 staining pattern were evaluated in combination, PR- tumors with IRS-2 at the membrane were associated with a significantly decreased OS when compared with all other combinations (P = 0.002). Evaluation of IRS-2 staining patterns could potentially be used to identify patients with PR- tumors who would most benefit from aggressive treatment.

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Figures

Fig. 1
Fig. 1
Analysis of IRS-2 antibody specificity. a MDA-MB-231 cells (control) and MDA-MB-231 cells expressing an IRS-2-specific shRNA (shIRS2) were fixed in formalin and embedded in paraffin. Sections were stained by IHC using an IRS-2-specific antibody (#1849, Epitomics). Magnification ×20. b Aliquots of cell lysates from MDA-MB-231 cells (C) and MDA-MB-231 cells expressing an IRS-2-specific shRNA (shIRS2) were immunoblotted for IRS-2 (#1849, Epitomics) and IRS-1 (#C20, Santa Cruz). c Immunohistochemical staining of human pancreas with rabbit IgG, IRS-1 (#C20, Santa Cruz), and IRS-2 (#1849, Epitomics). Magnification ×40
Fig. 2
Fig. 2
IRS expression in normal human breast tissue and benign breast lesions. Representative images of IRS-1 and -2 staining in normal ducts, fibroadenoma, usual ductal hyperplasia, sclerosing adenosis, and intraductal papilloma. Magnification ×20 for large images, ×40 for insets
Fig. 3
Fig. 3
IRS expression in human breast tumors and cell lines. a Representative images of IRS-1 and -2 staining in grade 1, grade 2, and grade 3 breast tumors. Magnification ×40 for all images. b Cytoplasmic (cyto) and nuclear (nuc) fractions from SUM-159PT and MDA-MB-231 breast carcinoma cells were immunoblotted with antibodies specific for IRS-1, IRS-2, GAPDH (cytoplasmic control), and hnRNP A1 (nuclear control)
Fig. 4
Fig. 4
IRS-2 localization in human breast tumors. a–c Representative images showing diffuse, punctate, and membrane IRS-2 staining patterns in breast tumors. Magnification ×40 for all images. d–i Representative images from the tissue microarray showing diffuse, punctate, and membrane IRS-2 staining patterns in breast tumor cores. Magnification ×20 (d–f), ×40 (g–i). j IRS-2 staining in a normal duct, adjacent DCIS, and invasive tumor within the same tissue section
Fig. 5
Fig. 5
Analysis of IRS-2 staining patterns, progesterone receptor status, and overall survival. a, c, e Kaplan–Meier survival curves showing overall survival (OS) in Set 1 (a), Set 2 (c), and the Pooled Set (e) for patients with tumors exhibiting IRS-2 staining at the membrane compared with non-membrane IRS-2 staining. P values for both univariate and multivariate analyses are shown. b, c, f Kaplan–Meier survival curves showing OS in tumors from Set 1 (b), Set 2 (d), and the Pooled Set (f) as a function of both progesterone receptor (PR) and IRS-2 membrane staining status. P values based on univariate analysis
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