Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression

Oncogene volume 36, pages 1394–1403 (2017)Cite this article

Subjects

Abstract

Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in vimentin protein expression in the MKR mice compared with WT. We hypothesized that vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral short hairpin RNA knockdown of vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented caspase 3 activation, and increased vimentin. Inhibiting the phosphatidylinositol 3 kinase/AKT pathway, using NVP-BKM120, increased active caspase 3 and decreased vimentin levels. This study is the first to show that vimentin has an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Redaniel MT, Jeffreys M, May MT, Ben-Shlomo Y, Martin RM . Associations of type 2 diabetes and diabetes treatment with breast cancer risk and mortality: a population-based cohort study among British women. Cancer Causes Control 2012; 23: 1785–1795.

    Article  PubMed  Google Scholar 

  2. Yang Y, Mauldin PD, Ebeling M, Hulsey TC, Liu B, Thomas MB et al. Effect of metabolic syndrome and its components on recurrence and survival in colon cancer patients. Cancer 2012; 119: 1512–1520.

    Article  PubMed  Google Scholar 

  3. Zanders MM, Boll D, van Steenbergen LN, van de Poll-Franse LV, Haak HR . Effect of diabetes on endometrial cancer recurrence and survival. Maturitas 2013; 74: 37–43.

    Article  PubMed  Google Scholar 

  4. Lawlor DA, Smith GD, Ebrahim S Hyperinsulinaemia and increased risk of breast cancer: findings from the British Women's Heart and Health Study. Cancer Causes Control 2004; 15: 267–275.

    Article  PubMed  Google Scholar 

  5. Ouchi N, Parker JL, Lugus JJ, Walsh K . Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 2002; 20: 42–51.

    Article  CAS  PubMed  Google Scholar 

  7. Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE . The impact of diabetes on survival following breast cancer. Breast Cancer Res Treat 2008; 109: 389–395.

    Article  PubMed  Google Scholar 

  8. DeFronzo RA . Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88: 787–835.

    Article  CAS  PubMed  Google Scholar 

  9. LeRoith D, Gavrilova O . Mouse models created to study the pathophysiology of type 2 diabetes. Int J Biochem Cell Biol 2006; 38: 904–912.

    Article  CAS  PubMed  Google Scholar 

  10. Fernandez AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL et al. Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev 2001; 15: 1926–1934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 2010; 70: 741–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ferguson RD, Novosyadlyy R, Fierz Y, Alikhani N, Sun H, Yakar S et al. Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes. Breast Cancer Res 2012; 14: R8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Franke WW, Grund C, Kuhn C, Jackson BW, Illmensee K . Formation of cytoskeletal elements during mouse embryogenesis. III. Primary mesenchymal cells and the first appearance of vimentin filaments. Differentiation 1982; 23: 43–59.

    Article  CAS  PubMed  Google Scholar 

  14. Thiery JP . Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442–454.

    Article  CAS  PubMed  Google Scholar 

  15. Mendez MG, Kojima S, Goldman RD . Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 2010; 24: 1838–1851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wei J, Xu G, Wu M, Zhang Y, Li Q, Liu P et al. Overexpression of vimentin contributes to prostate cancer invasion and metastasis via SRC regulation. Anticancer Res 2008; 28: 327–334.

    CAS  PubMed  Google Scholar 

  17. Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D . Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 2010; 59: 686–693.

    Article  CAS  PubMed  Google Scholar 

  18. Rostoker R, Abelson S, Bitton-Worms K, Genkin I, Ben-Shmuel S, Dakwar M et al. Highly specific role of the insulin receptor in breast cancer progression. Endocr Relat Cancer 2015; 22: 145–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Borowsky AD, Namba R, Young LJ, Hunter KW, Hodgson JG, Tepper CG et al. Syngeneic mouse mammary carcinoma cell lines: two closely related cell lines with divergent metastatic behavior. Clin Exp Metastasis 2005; 22: 47–59.

    Article  CAS  PubMed  Google Scholar 

  20. Samani AA, Yakar S, LeRoith D, Brodt P . The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007; 28: 20–47.

    Article  CAS  PubMed  Google Scholar 

  21. Zhu QS, Rosenblatt K, Huang KL, Lahat G, Brobey R, Bolshakov S et al. Vimentin is a novel AKT1 target mediating motility and invasion. Oncogene 2011; 30: 457–470.

    Article  CAS  PubMed  Google Scholar 

  22. Los M, Mozoluk M, Ferrari D, Stepczynska A, Stroh C, Renz A et al. Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol Biol Cell 2002; 13: 978–988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Adami HO, McLaughlin J, Ekbom A, Berne C, Silverman D, Hacker D et al. Cancer risk in patients with diabetes mellitus. Cancer Causes Control 1991; 2: 307–314.

    Article  CAS  PubMed  Google Scholar 

  24. Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM . Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005; 129: 504–511.

    Article  PubMed  Google Scholar 

  25. Onitilo AA, Engel JM, Glurich I, Stankowski RV, Williams GM, Doi SA . Diabetes and cancer I: risk, survival, and implications for screening. Cancer Causes Control 2012; 23: 967–981.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang PH, Chen ZW, Lv D, Xu YY, Gu WL, Zhang XH et al. Increased risk of cancer in patients with type 2 diabetes mellitus: a retrospective cohort study in China. BMC Public Health 2012; 12: 567.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Haslam DW, James WP . Obesity. Lancet 2005; 366: 1197–1209.

    Article  PubMed  Google Scholar 

  28. Gilles C, Polette M, Zahm JM, Tournier JM, Volders L, Foidart JM et al. Vimentin contributes to human mammary epithelial cell migration. J Cell Sci 1999; 112 (Pt 24): 4615–4625.

    CAS  PubMed  Google Scholar 

  29. Satelli A, Li S . Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 2011; 68: 3033–3046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shen X, Xi G, Wai C, Clemmons DR . The coordinate cellular response to insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-2 (IGFBP-2) is regulated through vimentin binding to receptor tyrosine phosphatase beta (RPTPbeta). J Biol Chem 2015; 290: 11578–11590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hines IN, Hartwell HJ, Feng Y, Theve EJ, Hall GA, Hashway S et al. Insulin resistance and metabolic hepatocarcinogenesis with parent-of-origin effects in AxB mice. Am J Pathol 2011; 179: 2855–2865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Svegliati-Baroni G, Faraci G, Fabris L, Saccomanno S, Cadamuro M, Pierantonelli I et al. Insulin resistance and necroinflammation drives ductular reaction and epithelial-mesenchymal transition in chronic hepatitis C. Gut 2011; 60: 108–115.

    Article  PubMed  Google Scholar 

  33. Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ, Feng YM . Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer 2014; 110: 724–732.

    Article  CAS  PubMed  Google Scholar 

  34. Ferguson RD, Gallagher EJ, Cohen D, Tobin-Hess A, Alikhani N, Novosyadlyy R et al. Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer. Endocr Relat Cancer 2013; 20: 391–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Colucci-Guyon E, Portier MM, Dunia I, Paulin D, Pournin S, Babinet C . Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 1994; 79: 679–694.

    Article  CAS  PubMed  Google Scholar 

  36. Eckes B, Colucci-Guyon E, Smola H, Nodder S, Babinet C, Krieg T et al. Impaired wound healing in embryonic and adult mice lacking vimentin. J Cell Sci 2000; 113 (Pt 13): 2455–2462.

    CAS  PubMed  Google Scholar 

  37. Eckes B, Dogic D, Colucci-Guyon E, Wang N, Maniotis A, Ingber D et al. Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts. J Cell Sci 1998; 111 (Pt 13): 1897–1907.

    CAS  PubMed  Google Scholar 

  38. Tezcan O, Gunduz U . Vimentin silencing effect on invasive and migration characteristics of doxorubicin resistant MCF-7 cells. Biomed Pharmacother 2014; 68: 357–364.

    Article  CAS  PubMed  Google Scholar 

  39. McInroy L, Maatta A . Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun 2007; 360: 109–114.

    Article  CAS  PubMed  Google Scholar 

  40. Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 2011; 30: 1436–1448.

    Article  CAS  PubMed  Google Scholar 

  41. Moore CB, Guthrie EH, Huang MT, Taxman DJ . Short hairpin RNA (shRNA): design, delivery, and assessment of gene knockdown. Methods Mol Biol 2010; 629: 141–158.

    PubMed  PubMed Central  Google Scholar 

  42. Beronja S, Livshits G, Williams S, Fuchs E . Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos. Nat Med 2010; 16: 821–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pei XF, Noble MS, Davoli MA, Rosfjord E, Tilli MT, Furth PA et al. Explant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice. In Vitro Cell Dev Biol Animal 2004; 40: 14–21.

    Article  Google Scholar 

  44. Cannata D, Lann D, Wu Y, Elis S, Sun H, Yakar S et al. Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology 2010; 151: 5751–5761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Marshall J . Transwell((R)) invasion assays. Methods Mol Biol 2011; 769: 97–110.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

NCI grant (grant 2R01CA128799-06A1) to DLR. American Diabetes grant 1-13-BS-108 to DLR. NIH/NCI 1K08CA190770 to EJG. NCI Supplement R01CA171558-02S1 to YD. Scuola di Specializzazione in Endocrinologia e Malattie del Metabolismo, University of Pisa to VB.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Z Zelenko, E J Gallagher, A Tobin-Hess, V Belardi, J Blank, Y Dina & D LeRoith

  2. Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, Israel

    R Rostoker & D LeRoith

Authors
  1. Z Zelenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E J Gallagher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Tobin-Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Belardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Rostoker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Blank
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Dina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D LeRoith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D LeRoith.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zelenko, Z., Gallagher, E., Tobin-Hess, A. et al. Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression. Oncogene 36, 1394–1403 (2017). https://doi.org/10.1038/onc.2016.305

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2016.305

This article is cited by

Search

Advanced search

Quick links