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:

WASF3 provides the conduit to facilitate invasion and metastasis in breast cancer cells through HER2/HER3 signaling

Oncogene volume 35, pages 4633–4640 (2016)Cite this article

Subjects

Abstract

The WASF3 gene is overexpressed in high-grade breast cancer and promotes invasion and metastasis, but does not affect proliferation. The HER2/ERBB2/NEU gene is also frequently overexpressed in breast cancer, and has been shown to promote invasion and metastasis in these tumors. Here, we show that WASF3 is present in the HER2 immunocomplex and suppression of WASF3 function leads to suppression of invasion even in the presence of HER2 expression. Overexpression of both HER2 and WASF3 in non-metastatic MCF7 breast cancer cells promotes invasion and metastasis more significantly than either gene alone. HER2 forms homodimers as well as heterodimers with other HER family members and we now show that the ability of WASF3 to promote invasion is highly dependent on the HER2/HER3 heterodimer. The engagement of WASF3 with the HER2/HER3 complex facilitates its phospho-activation and transcriptional upregulation, which is facilitated by HER2/HER3 activation of JAK/STAT signaling. In breast cancer cells overexpressing HER2, therefore, WASF3 is specifically required to facilitate the invasion/metastasis response. Targeting WASF3, therefore, could be a potential therapeutic approach to suppress metastasis of HER2-overexpressing breast tumors.

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

Similar content being viewed by others

References

  1. Sethi N, Kang Y . Unravelling the complexity of metastasis-molecular understanding and targeted therapies. Nat Rev Cancer 2011; 11: 735–748.

    Article  CAS  Google Scholar 

  2. Valastyan S, Weinberg RA . Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–292.

    Article  CAS  Google Scholar 

  3. Nguyen DX, Massagué J . Genetic determinants of cancer metastasis. Nat Rev Genet 2007; 8: 341–352.

    Article  CAS  Google Scholar 

  4. Gschwind A, Fischer OM, Ullrich A . The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004; 4: 361–370.

    Article  CAS  Google Scholar 

  5. Müller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwäble J et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res 2005; 65: 1778–1782.

    Article  Google Scholar 

  6. Mendelsohn J, Baselga J . Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003; 21: 2787–2799.

    Article  CAS  Google Scholar 

  7. Baselga J, Swain SM . Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer 2009; 9: 463–475.

    Article  CAS  Google Scholar 

  8. Tsujioka H, Yotsumoto F, Shirota K, Horiuchi S, Yoshizato T, Kuroki M et al. Emerging strategies for ErbB ligand-based targeted therapy for cancer. Anticancer Res 2010; 30: 3107–3112.

    CAS  PubMed  Google Scholar 

  9. Roses RE, Paulson EC, Sharma A, Schueller JE, Nisenbaum H, Weinstein S et al. HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer. Cancer Epidemiol Biomarkers Prev 2009; 18: 1386–1389.

    Article  CAS  Google Scholar 

  10. van de Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans J, Dalesio O et al. Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 1988; 319: 1239–1245.

    Article  CAS  Google Scholar 

  11. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010; 28: 3271–3277.

    Article  Google Scholar 

  12. Freudenberg JA, Wang Q, Katsumata M, Drebin J, Nagatomo I, Greene MI . The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies. Exp Mol Pathol 2009; 87: 1–11.

    Article  CAS  Google Scholar 

  13. Johnson E, Seachrist DD, DeLeon-Rodriguez CM, Lozada KL, Miedler J, Abdul-Karim FW et al. HER2/ErbB2-induced breast cancer cell migration and invasion require p120 catenin activation of Rac1 and Cdc42. J Biol Chem 2010; 285: 29491–29501.

    Article  CAS  Google Scholar 

  14. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008; 68: 5878–5887.

    Article  CAS  Google Scholar 

  15. Vaught DB, Stanford JC, Young C, Hicks DJ, Wheeler F, Rinehart C et al. HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res 2012; 72: 2672–2682.

    Article  CAS  Google Scholar 

  16. Liu J, Kern JA . Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol 2002; 27: 306–313.

    Article  CAS  Google Scholar 

  17. Shankaran H, Wiley HS, Resat H . Modeling the effects of HER/ErbB1-3 coexpression on receptor dimerization and biological response. Biophys J 2006; 90: 3993–4009.

    Article  CAS  Google Scholar 

  18. Bosc DG, Goueli BS, Janknecht R . HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. Oncogene 2001; 20: 6215–6224.

    Article  CAS  Google Scholar 

  19. Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM . Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 2004; 10: 7621–7628.

    Article  CAS  Google Scholar 

  20. Sossey-Alaoui K, Su G, Malaj E, Roe B, Cowell JK . WAVE3, an actin-polymerization gene, is truncated and inactivated as a result of a constitutional t(1;13)(q21;q12) chromosome translocation in a patient with ganglioneuroblastoma. Oncogene 2002; 21: 5967–5974.

    Article  CAS  Google Scholar 

  21. Sossey-Alaoui K . Surfing the big WAVE: Insights into the role of WAVE3 as a driving force in cancer progression and metastasis. Semin Cell Dev Biol 2013; 24: 287–297.

    CAS  PubMed  Google Scholar 

  22. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010; 12: R68.

    Article  Google Scholar 

  23. Teng Y, Liu M, Cowell JK . Functional interrelationship between the WASF3 and KISS1 metastasis-associated genes in breast cancer cells. Int J Cancer 2011; 129: 2825–2835.

    Article  CAS  Google Scholar 

  24. Ghoshal P, Teng Y, Lesoon L, Cowell JK . HIF1A induces expression of the WASF3 metastasis associated gene under hypoxic conditions. Int J Cancer 2012; 131: E905–E915.

    Article  CAS  Google Scholar 

  25. Teng Y, Ngoka L, Mei Y, Lesoon L, Cowell JK . HSP90 and HSP70 are essential for stabilization and activation of the WASF3 metastasis promoting protein. J Biol Chem 2012; 287: 10051–10059.

    Article  CAS  Google Scholar 

  26. Teng Y, Ghoshal P, Ngoka L, Mei Y, Cowell JK . Critical role of the WASF3 gene in JAK2/STAT3 regulation of cancer cell invasion. Carcinogenesis 2013; 4: 1994–1999.

    Article  Google Scholar 

  27. Teng Y, Xie X, Walker S, White DT, Mumm JS, Cowell JK . Evaluating human cancer cell metastasis in zebrafish. BMC Cancer 2013; 13: 453.

    Article  Google Scholar 

  28. Teng Y, Mei Y, Hawthorn LA, Cowell JK . WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells. Oncogene 2014; 33: 203–211.

    Article  CAS  Google Scholar 

  29. Teng Y, Ross JL, Cowell JK . The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT 2014; 3: e28086.

    PubMed  PubMed Central  Google Scholar 

  30. Teng Y, Ren X, Li H, Shull A, Kim J, Cowell JK . Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein. Oncogene 2015, e-pub ahead of print 30 March 2015; doi:10.1038/onc.2015.86.

    Article  Google Scholar 

  31. Sossey-Alaoui K, Li X, Ranalli TA, Cowell JK . WAVE3-mediated cell migration and lamellipodia formation are regulated downstream of phosphatidylinositol 3-kinase. J Biol Chem 2005; 280: 21748–21755.

    Article  CAS  Google Scholar 

  32. Sossey-Alaoui K, Li X, Cowell JK . c-Abl-mediated phosphorylation of WAVE3 is required for lamellipodia formation and cell migration. J Biol Chem 2007; 282: 26257–26265.

    Article  CAS  Google Scholar 

  33. Atalay G, Cardoso F, Awada A, Piccart MJ . Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer. Ann Oncol 2003; 14: 1346–1363.

    Article  CAS  Google Scholar 

  34. Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 2011; 17: 132–139.

    Article  Google Scholar 

  35. Basso AD, Solit DB, Munster PN, Rosen N . Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene 2002; 21: 1159–1166.

    Article  CAS  Google Scholar 

  36. Barok M, Joensuu H, Isola J . Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res 2014; 16: 209.

    Article  Google Scholar 

  37. Gomez-Martín C, Lopez-Rios F, Aparicio J, Barriuso J, García-Carbonero R, Pazo R et al. A critical review of HER2-positive gastric cancer evaluation and treatment: from trastuzumab, and beyond. Cancer Lett 2014; 351: 30–40.

    Article  Google Scholar 

  38. Teng Y, Ren M, Cheney R, Sharma S, Cowell JK . Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases. Br J Cancer 2010; 103: 1066–1075.

    Article  CAS  Google Scholar 

  39. Taylor MA, Davuluri G, Parvani JG, Schiemann BJ, Wendt MK, Plow EF et al. Upregulated WAVE3 expression is essential for TGF-β-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat 2013; 142: 341–353.

    Article  CAS  Google Scholar 

  40. Takenawa T, Suetsugu S . The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007; 8: 37–48.

    Article  CAS  Google Scholar 

  41. Teng Y, Bahassan A, Dong DY, Hanold LE, Ren X, Kennedy EJ et al. Targeting the WASF3-CYFIP1 complex using stapled peptides suppresses cancer cell invasion. Cancer Res 2015, e-pub ahead of print 16 December 2015.

  42. Zhang J, Zhou S, Tang L, Shen L, Xiao L, Duan Z et al. WAVE1 gene silencing via RNA interference reduces ovarian cancer cell invasion, migration and proliferation. Gynecol Oncol 2013; 130: 354–361.

    Article  CAS  Google Scholar 

  43. Cai Z, Zhang G, Zhou Z, Bembas K, Drebin JA, Greene MI et al. Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene 2008; 27: 3870–3874.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grant CA120510 from the National Institutes of Health. We would like to thank Yun Mei and Hao Zhang for the technical assistance.

Author information

Authors and Affiliations

  1. Cancer Center, Georgia Regents University, Augusta, GA, USA

    Y Teng, Y Wang & J K Cowell

  2. Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, USA

    Y Teng & W Pi

Authors
  1. Y Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W Pi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J K Cowell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Teng.

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

Teng, Y., Pi, W., Wang, Y. et al. WASF3 provides the conduit to facilitate invasion and metastasis in breast cancer cells through HER2/HER3 signaling. Oncogene 35, 4633–4640 (2016). https://doi.org/10.1038/onc.2015.527

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.527

This article is cited by

Search

Advanced search

Quick links