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:

Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon

Oncogene volume 28, pages 431–444 (2009)Cite this article

Abstract

11q13 amplification is a late-stage event in several cancers that is often associated with poor prognosis. Among 11q13-amplified genes, the actin assembly protein cortactin/CTTN is considered a likely candidate for direct involvement in tumor progression because of its cell motility-enhancing functions. We modulated cortactin expression in head and neck squamous cell carcinoma (HNSCC) cell lines. Cortactin expression levels directly correlated with tumor size, vascularization and cell proliferation in an orthotopic HNSCC in vivo model. In contrast, under normal in vitro culture conditions, cortactin expression levels had no effect on cell proliferation. However, cell lines in which cortactin expression was reduced by knockdown (KD) grew poorly in vitro under harsh conditions of growth factor deprivation, anchorage independence and space constraint. In contrast, overexpression of cortactin enhanced in vitro growth under the same harsh conditions. Surprisingly, defects in growth factor-independent proliferation of cortactin-KD cells were rescued by coculture with cortactin-expressing cells. As the cocultured cells are separated by permeable filters, cortactin-expressing cells must secrete growth-supporting autocrine factors to rescue the cortactin-KD cells. Overall, cortactin expression modulates multiple cellular traits that may allow survival in a tumor environment, suggesting that the frequent overexpression of cortactin in tumors is not an epiphenomenon but rather promotes tumor aggressiveness.

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

Similar content being viewed by others

References

  • Akervall JA, Jin Y, Wennerberg JP, Zatterstrom UK, Kjellen E, Mertens F et al. (1995). Chromosomal abnormalities involving 11q13 are associated with poor prognosis in patients with squamous cell carcinoma of the head and neck. Cancer 76: 853–859.

    Article  CAS  Google Scholar 

  • Bates SE, Valverius EM, Ennis BW, Bronzert DA, Sheridan JP, Stampfer MR et al. (1990). Expression of the transforming growth factor-alpha/epidermal growth factor receptor pathway in normal human breast epithelial cells. Endocrinology 126: 596–607.

    Article  CAS  Google Scholar 

  • Bryce NS, Clark ES, Leysath JL, Currie JD, Webb DJ, Weaver AM . (2005). Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr Biol 15: 1276–1285.

    Article  CAS  Google Scholar 

  • Cao H, Orth JD, Chen J, Weller SG, Heuser JE, McNiven MA . (2003). Cortactin is a component of clathrin-coated pits and participates in receptor-mediated endocytosis. Mol Cell Biol 23: 2162–2170.

    Article  CAS  Google Scholar 

  • Cao H, Weller S, Orth JD, Chen J, Huang B, Chen JL et al. (2005). Actin and Arf1-dependent recruitment of a cortactin–dynamin complex to the Golgi regulates post-Golgi transport. Nat Cell Biol 7: 483–492.

    Article  CAS  Google Scholar 

  • Chuma M, Sakamoto M, Yasuda J, Fujii G, Nakanishi K, Tsuchiya A et al. (2004). Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma. J Hepatol 41: 629–636.

    Article  CAS  Google Scholar 

  • Clark ES, Weaver AM . (2008). A new role for cortactin in invadopodia: regulation of protease secretion. Eur J Cell Biol 87: 581–590.

    Article  CAS  Google Scholar 

  • Clark ES, Whigham AS, Yarbrough WG, Weaver AM . (2007). Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res 67: 4227–4235.

    Article  CAS  Google Scholar 

  • Debnath J, Brugge JS . (2005). Modelling glandular epithelial cancers in three-dimensional cultures. Nat Rev Cancer 5: 675–688.

    Article  CAS  Google Scholar 

  • Debnath J, Muthuswamy SK, Brugge JS . (2003). Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30: 256–268.

    Article  CAS  Google Scholar 

  • Ethier SP, Langton BC, Dilts CA . (1996). Growth factor-independent proliferation of rat mammary carcinoma cells by autocrine secretion of neu-differentiation factor/heregulin and transforming growth factor-alpha. Mol Carcinog 15: 134–143.

    Article  CAS  Google Scholar 

  • Ethier SP, Moorthy R, Dilts CA . (1991). Secretion of an epidermal growth factor-like growth factor by epidermal growth factor-independent rat mammary carcinoma cells. Cell Growth Differ 2: 593–602.

    CAS  PubMed  Google Scholar 

  • Freier K, Sticht C, Hofele C, Flechtenmacher C, Stange D, Puccio L et al. (2006). Recurrent coamplification of cytoskeleton-associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma. Genes Chromosomes Cancer 45: 118–125.

    Article  CAS  Google Scholar 

  • Gabrilove JL . (2001). Angiogenic growth factors: autocrine and paracrine regulation of survival in hematologic malignancies. Oncologist 6 (Suppl 5): 4–7.

    Article  CAS  Google Scholar 

  • Gibcus JH, Mastik MF, Menkema L, de Bock GH, Kluin PM, Schuuring E et al. (2008). Cortactin expression predicts poor survival in laryngeal carcinoma. Br J Cancer 98: 950–955.

    Article  CAS  Google Scholar 

  • Gibcus JH, Menkema L, Mastik MF, Hermsen MA, de Bock GH, van Velthuysen ML et al. (2007). Amplicon mapping and expression profiling identify the Fas-associated death domain gene as a new driver in the 11q13.3 amplicon in laryngeal/pharyngeal cancer. Clin Cancer Res 13: 6257–6266.

    Article  CAS  Google Scholar 

  • Greer Jr RO, Said S, Shroyer KR, Marileila VG, Weed SA . (2007). Overexpression of cyclin D1 and cortactin is primarily independent of gene amplification in salivary gland adenoid cystic carcinoma. Oral Oncol 43: 735–741.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Hiratsuka S, Watanabe A, Aburatani H, Maru Y . (2006). Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8: 1369–1375.

    Article  CAS  Google Scholar 

  • Hofman P, Butori C, Havet K, Hofman V, Selva E, Guevara N et al. (2008). Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status. Br J Cancer 98: 956–964.

    Article  CAS  Google Scholar 

  • Hui R, Ball JR, Macmillan RD, Kenny FS, Prall OW, Campbell DH et al. (1998). EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival. Oncogene 17: 1053–1059.

    Article  CAS  Google Scholar 

  • Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449: 557–563.

    Article  CAS  Google Scholar 

  • Katsube T, Togashi S, Hashimoto N, Ogiu T, Tsuji H . (2004). Filamentous actin binding ability of cortactin isoforms is responsible for their cell-cell junctional localization in epithelial cells. Arch Biochem Biophys 427: 79–90.

    Article  CAS  Google Scholar 

  • Li Y, Tondravi M, Liu J, Smith E, Haudenschild CC, Kaczmarek M et al. (2001). Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res 61: 6906–6911.

    CAS  Google Scholar 

  • Luo ML, Shen XM, Zhang Y, Wei F, Xu X, Cai Y et al. (2006). Amplification and overexpression of CTTN (EMS1) contribute to the metastasis of esophageal squamous cell carcinoma by promoting cell migration and anoikis resistance. Cancer Res 66: 11690–11699.

    Article  CAS  Google Scholar 

  • Markowitz SD, Molkentin K, Gerbic C, Jackson J, Stellato T, Willson JK . (1990). Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium. J Clin Invest 86: 356–362.

    Article  CAS  Google Scholar 

  • Meredith SD, Levine PA, Burns JA, Gaffey MJ, Boyd JC, Weiss LM et al. (1995). Chromosome 11q13 amplification in head and neck squamous cell carcinoma. Association with poor prognosis. Arch Otolaryngol Head Neck Surg 121: 790–794.

    Article  CAS  Google Scholar 

  • Merrifield CJ, Perrais D, Zenisek D . (2005). Coupling between clathrin-coated-pit invagination, cortactin recruitment, and membrane scission observed in live cells. Cell 121: 593–606.

    Article  CAS  Google Scholar 

  • Myllykangas S, Bohling T, Knuutila S . (2007). Specificity, selection and significance of gene amplifications in cancer. Semin Cancer Biol 17: 42–55.

    Article  CAS  Google Scholar 

  • Ohoka Y, Takai Y . (1998). Isolation and characterization of cortactin isoforms and a novel cortactin-binding protein, CBP90. Genes Cells 3: 603–612.

    Article  CAS  Google Scholar 

  • Ormandy CJ, Musgrove EA, Hui R, Daly RJ, Sutherland RL . (2003). Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 78: 323–335.

    Article  CAS  Google Scholar 

  • Ostman A . (2004). PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 15: 275–286.

    Article  Google Scholar 

  • Rangan SR . (1972). A new human cell line (FaDu) from a hypopharyngeal carcinoma. Cancer 29: 117–121.

    Article  CAS  Google Scholar 

  • Rodrigo JP, Garcia LA, Ramos S, Lazo PS, Suarez C . (2000). EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res 6: 3177–3182.

    CAS  PubMed  Google Scholar 

  • Schuuring E, Verhoeven E, Mooi WJ, Michalides RJ . (1992). Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene 7: 355–361.

    CAS  PubMed  Google Scholar 

  • Schuuring E . (1995). The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes—a review. Gene 159: 83–96.

    Article  CAS  Google Scholar 

  • Shores CG, Yarbrough WG . (1998). Three-dimensional xenograft model of dysplastic human laryngeal mucosa. Laryngoscope 108: 1358–1362.

    Article  CAS  Google Scholar 

  • Somers KD, Cartwright SL, Schechter GL . (1990). Amplification of the int-2 gene in human head and neck squamous cell carcinomas. Oncogene 5: 915–920.

    CAS  PubMed  Google Scholar 

  • Takes RP, Baatenburg de Jong RJ, Schuuring E, Hermans J, Vis AA, Litvinov SV et al. (1997). Markers for assessment of nodal metastasis in laryngeal carcinoma. Arch Otolaryngol Head Neck Surg 123: 412–419.

    Article  CAS  Google Scholar 

  • Tsao MS, Zhu H, Viallet J . (1996). Autocrine growth loop of the epidermal growth factor receptor in normal and immortalized human bronchial epithelial cells. Exp Cell Res 223: 268–273.

    Article  CAS  Google Scholar 

  • Uruno T, Liu J, Zhang P, Fan Yx, Egile C, Li R et al. (2001). Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nat Cell Biol 3: 259–266.

    Article  CAS  Google Scholar 

  • van Rossum AG, van Bragt MP, Schuuring-Scholtes E, van der Ploeg JC, van Krieken JH, Kluin PM et al. (2006). Transgenic mice with mammary gland targeted expression of human cortactin do not develop (pre-malignant) breast tumors: studies in MMTV-cortactin and MMTV-cortactin/-cyclin D1 bitransgenic mice. BMC Cancer 6: 58.

    Article  Google Scholar 

  • Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT et al. (2001). Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr Biol 11: 370–374.

    Article  CAS  Google Scholar 

  • Weaver AM . (2008). Cortactin in tumor invasiveness. Cancer Lett 265: 157–166.

    Article  CAS  Google Scholar 

  • Weichselbaum RR, Dahlberg W, Beckett M, Karrison T, Miller D, Clark J et al. (1986). Radiation-resistant and repair-proficient human tumor cells may be associated with radiotherapy failure in head- and neck-cancer patients. Proc Natl Acad Sci USA 83: 2684–2688.

    Article  CAS  Google Scholar 

  • Williams ME, Gaffey MJ, Weiss LM, Wilczynski SP, Schuuring E, Levine PA . (1993). Chromosome 11Q13 amplification in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 119: 1238–1243.

    Article  CAS  Google Scholar 

  • Wu H, Parsons JT . (1993). Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex. J Cell Biol 120: 1417–1426.

    Article  CAS  Google Scholar 

  • Wu H, Reynolds AB, Kanner SB, Vines RR, Parsons JT . (1991). Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol Cell Biol 11: 5113–5124.

    Article  CAS  Google Scholar 

  • Yuan BZ, Zhou X, Zimonjic DB, Durkin ME, Popescu NC . (2003). Amplification and overexpression of the EMS 1 oncogene, a possible prognostic marker, in human hepatocellular carcinoma. J Mol Diagn 5: 48–53.

    Article  CAS  Google Scholar 

  • Zhu J, Zhou K, Hao JJ, Liu J, Smith N, Zhan X . (2005). Regulation of cortactin/dynamin interaction by actin polymerization during the fission of clathrin-coated pits. J Cell Sci 118: 807–817.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Julie Maier, Izu Iwueke and the IHC core for technical support; and Drs Ambra Pozzi and Vito Quaranta for advice. This work was supported by 1R21DE018244 to AMW. WGY, BB, ASW, and AK are partially supported through a grant from the Robert J Kleberg Jr and Helen C Kleberg Foundation. An endowment supporting the Barry Baker Laboratory for Head and Neck Oncology as well as the Robert J Kleberg Jr and Helen C Kleberg Foundation and an Ingram Professorship to WGY also provided support for this project.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA

    E S Clark, W G Yarbrough & A M Weaver

  2. Department of Otolaryngology, Vanderbilt University, Nashville, TN, USA

    B Brown, A S Whigham, A Kochaishvili & W G Yarbrough

  3. Department of Pathology, Vanderbilt University, Nashville, TN, USA

    A M Weaver

Authors
  1. E S Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A S Whigham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Kochaishvili
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W G Yarbrough
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A M Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A M Weaver.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, E., Brown, B., Whigham, A. et al. Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon. Oncogene 28, 431–444 (2009). https://doi.org/10.1038/onc.2008.389

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.389

Keywords

This article is cited by

Search

Advanced search

Quick links