Breast Cancer Research and Treatment

, Volume 130, Issue 3, pp 759–772

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

  • Jennifer L. Clark
  • Karen Dresser
  • Chung-Cheng Hsieh
  • Michael Sabel
  • Celina G. Kleer
  • Ashraf Khan
  • Leslie M. Shaw
Preclinical study


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.


IRS proteins Breast cancer Progesterone receptor IGF-1 receptor 

Supplementary material

10549_2011_1353_MOESM1_ESM.pdf (34 kb)
Supplementary material 1 (PDF 34 kb)
10549_2011_1353_MOESM2_ESM.pdf (22 kb)
Supplemental Fig. 1 Analysis of IRS-2 diffuse staining pattern, 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 diffuse staining compared with non-diffuse 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 diffuse staining status. P values based on univariate analysis. (PDF 21 kb)
10549_2011_1353_MOESM3_ESM.pdf (22 kb)
Supplemental Fig. 2 Analysis of IRS-2 punctate staining pattern, 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 punctate staining compared with non-punctate 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 punctate staining status. P values based on univariate analysis. (PDF 21 kb)


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Jennifer L. Clark
    • 1
  • Karen Dresser
    • 2
  • Chung-Cheng Hsieh
    • 1
  • Michael Sabel
    • 3
  • Celina G. Kleer
    • 4
  • Ashraf Khan
    • 2
  • Leslie M. Shaw
    • 1
  1. 1.Department of Cancer BiologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of PathologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Department of SurgeryUniversity of Michigan Health SystemAnn ArborUSA
  4. 4.Department of PathologyUniversity of Michigan Health SystemAnn ArborUSA

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