Skip to main content

Advertisement

SpringerLink
Log in

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

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Furlanetto RW, DiCarlo JN (1984) Somatomedin-C receptors and growth effects in human breast cells maintained in long-term tissue culture. Cancer Res 44(5):2122–2128

    PubMed  CAS  Google Scholar 

  2. Turner BC, Haffty BG, Narayanan L, Yuan J, Havre PA, Gumbs AA, Kaplan L, Burgaud JL, Carter D, Baserga R, Glazer PM (1997) Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 57(15):3079–3083

    PubMed  CAS  Google Scholar 

  3. Johnston SR, Dowsett M, Smith IE (1992) Towards a molecular basis for tamoxifen resistance in breast cancer. Ann Oncol 3(7):503–511

    PubMed  CAS  Google Scholar 

  4. Resnik JL, Reichart DB, Huey K, Webster NJ, Seely BL (1998) Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res 58(6):1159–1164

    PubMed  CAS  Google Scholar 

  5. White MF, Maron R, Kahn CR (1985) Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185, 000 protein in intact cells. Nature 318(6042):183–186

    Article  PubMed  CAS  Google Scholar 

  6. Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR (1995) 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. J Biol Chem 270(42):24670–24673

    Article  PubMed  CAS  Google Scholar 

  7. Yamauchi T, Kaburagi Y, Ueki K, Tsuji Y, Stark GR, Kerr IM, Tsushima T, Akanuma Y, Komuro I, Tobe K, Yazaki Y, Kadowaki T (1998) Growth hormone and prolactin stimulate tyrosine phosphorylation of insulin receptor substrate-1, -2, and -3, their association with p85 phosphatidylinositol 3-kinase (PI3-kinase), and concomitantly PI3-kinase activation via JAK2 kinase. J Biol Chem 273(25):15719–15726

    Article  PubMed  CAS  Google Scholar 

  8. Mardilovich K, Pankratz S, Shaw L (2009) Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal 7(1):14

    Article  PubMed  Google Scholar 

  9. White MF (1996) The IRS-signalling system in insulin and cytokine action. Philos Trans R Soc Lond B Biol Sci 351(1336):181–189

    Article  PubMed  CAS  Google Scholar 

  10. Ma Z, Gibson SL, Byrne MA, Zhang J, White MF, Shaw LM (2006) Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Mol Cell Biol 26(24):9338–9351

    Article  PubMed  CAS  Google Scholar 

  11. Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM (2004) Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 24(22):9726–9735

    Article  PubMed  CAS  Google Scholar 

  12. Gibson SL, Ma Z, Shaw LM (2007) Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. Cell Cycle 6(6):631–637

    Article  PubMed  CAS  Google Scholar 

  13. Byron SA, Horwitz KB, Richer JK, Lange CA, Zhang X, Yee D (2006) Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. Br J Cancer 95(9):1220–1228

    Article  PubMed  CAS  Google Scholar 

  14. Jackson JG, Zhang X, Yoneda T, Yee D (2001) Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. Oncogene 20(50):7318–7325

    Article  PubMed  CAS  Google Scholar 

  15. Zhang X, Kamaraju S, Hakuno F, Kabuta T, Takahashi S, Sachdev D, Yee D (2004) Motility response to insulin-like growth factor-I (IGF-I) in MCF-7 cells is associated with IRS-2 activation and integrin expression. Breast Cancer Res Treat 83(2):161–170. doi:10.1023/B:BREA.0000010709.31256.c6

    Article  PubMed  CAS  Google Scholar 

  16. Ibrahim YH, Byron SA, Cui X, Lee AV, Yee D (2008) Progesterone receptor-B regulation of insulin-like growth factor-stimulated cell migration in breast cancer cells via insulin receptor substrate-2. Mol Cancer Res 6(9):1491–1498

    Article  PubMed  CAS  Google Scholar 

  17. Pankratz SL, Tan EY, Fine Y, Mercurio AM, Shaw LM (2009) Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1. J Biol Chem 284(4):2031–2037

    Article  PubMed  CAS  Google Scholar 

  18. Giovannone B, Scaldaferri ML, Federici M, Porzio O, Lauro D, Fusco A, Sbraccia P, Borboni P, Lauro R, Sesti G (2000) Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential. Diabetes Metab Res Rev 16(6):434–441

    Article  PubMed  CAS  Google Scholar 

  19. Lee AV, Zhang P, Ivanova M, Bonnette S, Oesterreich S, Rosen JM, Grimm S, Hovey RC, Vonderhaar BK, Kahn CR, Torres D, George J, Mohsin S, Allred DC, Hadsell DL (2003) Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland. Endocrinology 144(6):2683–2694

    Article  PubMed  CAS  Google Scholar 

  20. Sisci D, Morelli C, Garofalo C, Romeo F, Morabito L, Casaburi F, Middea E, Cascio S, Brunelli E, Andò S, Surmacz E (2007) Expression of nuclear insulin receptor substrate 1 in breast cancer. J Clin Pathol 60(6):633–641

    Article  PubMed  CAS  Google Scholar 

  21. Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D (1999) Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol 13(5):787–796

    Article  PubMed  CAS  Google Scholar 

  22. Molloy CA, May FE, Westley BR (2000) Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line. J Biol Chem 275(17):12565–12571

    Article  PubMed  CAS  Google Scholar 

  23. Mauro L, Salerno M, Panno ML, Bellizzi D, Sisci D, Miglietta A, Surmacz E, Andò S (2001) Estradiol increases IRS-1 gene expression and insulin signaling in breast cancer cells. Biochem Biophys Res Commun 288(3):685–689

    Article  PubMed  CAS  Google Scholar 

  24. Koda M, Sulkowska M, Kanczuga-Koda L, Sulkowski S (2005) Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases. J Clin Pathol 58(6):645–649

    Article  PubMed  CAS  Google Scholar 

  25. Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D (2000) Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 89(6):506–513

    Article  PubMed  CAS  Google Scholar 

  26. Vassen L, Wegrzyn W, Klein-Hitpass L (1999) Human insulin receptor substrate-2 (IRS-2) is a primary progesterone response gene. Mol Endocrinol 13(3):485–494

    Article  PubMed  CAS  Google Scholar 

  27. Cui X, Kim H, Kuiatse I, Kim H, Brown PH, Lee AV (2006) Epidermal growth factor induces insulin receptor substrate-2 in breast cancer cells via c-Jun NH(2)-terminal kinase/activator protein-1 signaling to regulate cell migration. Cancer Res 66(10):5304–5313

    Article  PubMed  CAS  Google Scholar 

  28. Mardilovich K, Shaw LM (2009) Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion. Cancer Res 69(23):8894–8901

    Article  PubMed  CAS  Google Scholar 

  29. Morelli C, Garofalo C, Sisci D, del Rincon S, Cascio S, Tu X, Vecchione A, Sauter ER, Miller WH, Surmacz E (2004) Nuclear insulin receptor substrate 1 interacts with estrogen receptor alpha at ERE promoters. Oncogene 23(45):7517–7526

    Article  PubMed  CAS  Google Scholar 

  30. Migliaccio I, Wu M, Gutierrez C, Malorni L, Mohsin S, Allred D, Hilsenbeck S, Osborne C, Weiss H, Lee A (2009) Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer. Breast Cancer Res Treat 123(3):651–660. doi:10.1007/s10549-009-0632-6

    Article  PubMed  Google Scholar 

  31. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins S, Ghosh D, Sewalt R, Otte A, Hayes D, Sabel M, Livant D, Weiss S, Rubin M, Chinnaiyan A (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 100(20):11606–11611

    Article  PubMed  CAS  Google Scholar 

  32. McShane L, Altman D, Sauerbrei W, Taube S, Gion M, Clark G, Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235. doi:10.1007/s10549-006-9242-8

    Article  PubMed  Google Scholar 

  33. Prisco M, Santini F, Baffa R, Liu M, Drakas R, Wu A, Baserga R (2002) Nuclear translocation of insulin receptor substrate-1 by the simian virus 40 T antigen and the activated type 1 insulin-like growth factor receptor. J Biol Chem 277(35):32078–32085

    Article  PubMed  CAS  Google Scholar 

  34. Thirone ACP, Scarlett JA, Gasparetti AL, Araujo EP, Lima MHL, Carvalho CRO, Velloso LA, Saad MJA (2002) Modulation of growth hormone signal transduction in kidneys of streptozotocin-induced diabetic animals: effect of a growth hormone receptor antagonist. Diabetes 51(7):2270–22781

    Article  PubMed  CAS  Google Scholar 

  35. Chen J, Wu A, Sun H, Drakas R, Garofalo C, Cascio S, Surmacz E, Baserga R (2005) Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and beta-catenin. J Biol Chem 280(33):29912–29920

    Article  PubMed  CAS  Google Scholar 

  36. Lanzino M, Garofalo C, Morelli C, Le Pera M, Casaburi I, McPhaul MJ, Surmacz E, Andò S, Sisci D (2009) Insulin receptor substrate 1 modulates the transcriptional activity and the stability of androgen receptor in breast cancer cells. Breast Cancer Res Treat 115(2):297–306. doi:10.1007/s10549-008-0079-1

    Article  PubMed  CAS  Google Scholar 

  37. Wu A, Chen J, Baserga R (2008) Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes. Oncogene 27(3):397–403

    Article  PubMed  CAS  Google Scholar 

  38. Petrie RJ, Doyle AD, Yamada KM (2009) Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10(8):538–549

    Article  PubMed  CAS  Google Scholar 

  39. Monami G, Emiliozzi V, Morrione A (2008) Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J Cell Physiol 216(2):426–437

    Article  PubMed  CAS  Google Scholar 

  40. Romanelli RJ, LeBeau AP, Fulmer CG, Lazzarino DA, Hochberg A, Wood TL (2007) Insulin-like growth factor type-I receptor internalization and recycling mediate the sustained phosphorylation of Akt. J Biol Chem 282(31):22513–22524

    Article  PubMed  CAS  Google Scholar 

  41. Gross GE, Clark GM, Chamness GC, McGuire WL (1984) Multiple progesterone receptor assays in human breast cancer. Cancer Res 44(2):836–840

    PubMed  CAS  Google Scholar 

  42. Balleine RL, Earl MJ, Greenberg ML, Clarke CL (1999) Absence of progesterone receptor associated with secondary breast cancer in postmenopausal women. Br J Cancer 79(9–10):1564–1571

    Article  PubMed  CAS  Google Scholar 

  43. Anderson WF, Chu KC, Chatterjee N, Brawley O, Brinton LA (2001) Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database. J Clin Oncol 19(1):18–27

    PubMed  CAS  Google Scholar 

  44. Arpino G, Weiss H, Lee AV, Schiff R, De Placido S, Osborne CK, Elledge RM (2005) Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97(17):1254–1261

    Article  PubMed  CAS  Google Scholar 

  45. Cui X, Schiff R, Arpino G, Osborne CK, Lee AV (2005) Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol 23(30):7721–7735

    Article  PubMed  CAS  Google Scholar 

  46. Singh A, Ali S, Kothari MS, De Bella MT, Smith C, Timms E, Slade MJ, Foxwell BM, Coombes RC (2003) Reporter gene assay demonstrates functional differences in estrogen receptor activity in purified breast cancer cells: a pilot study. Int J Cancer 107(5):700–706

    Article  PubMed  CAS  Google Scholar 

  47. Cui X, Zhang P, Deng W, Oesterreich S, Lu Y, Mills GB, Lee AV (2003) Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol 17(4):575–588

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by National Institute of Health (NIH) grants CA090583 and CA142782 (LMS); Department of Defense Synergistic Idea Award W81XWH-07-1-0599 (LMS and AK); National Institute of Health grants CA125577, CA107469, and CA154224 (CGK); and Department of Defense Breast Cancer Predoctoral Fellowship W81XWH-10-1-0038 (JLC). LMS is a member of the University of Massachusetts Diabetes and Endocrinology Research Center (DERC) (DK32520) and the University of Massachusetts Memorial Cancer Center of Excellence. We thank Dr. Qin Liu at the University of Massachusetts Medical School for her advice on statistical analysis.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA, 01605, USA

    Jennifer L. Clark, Chung-Cheng Hsieh & Leslie M. Shaw

  2. Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Karen Dresser & Ashraf Khan

  3. Department of Surgery, University of Michigan Health System, Ann Arbor, MI, 48109, USA

    Michael Sabel

  4. Department of Pathology, University of Michigan Health System, Ann Arbor, MI, 48109, USA

    Celina G. Kleer

Authors
  1. Jennifer L. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen Dresser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chung-Cheng Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Sabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Celina G. Kleer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ashraf Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leslie M. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leslie M. Shaw.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 34 kb)

10549_2011_1353_MOESM2_ESM.pdf

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

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, J.L., Dresser, K., Hsieh, CC. et al. Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer. Breast Cancer Res Treat 130, 759–772 (2011). https://doi.org/10.1007/s10549-011-1353-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1353-1

Keywords

Search

Navigation