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.

  • Article
  • Published:

The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer

Oncogene volume 39, pages 2258–2274 (2020)Cite this article

Subjects

Abstract

Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/β-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/β-catenin signaling pathway, and activation of Wnt/β-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of β-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, β-catenin, and TCF4 can form VASP/DVL3/β-catenin/TCF4 protein complex, activating Wnt/β-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc, and cyclin D1. Thus, our study reveals that there is a Wnt/β-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.

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

Fig. 1: VASP is a target gene of Wnt/β-catenin signaling pathway.
Fig. 2: The expression of VASP in breast cancer tissues is increased and closely related to the clinicopathological features of breast cancer.
Fig. 3: In breast cancer cells, VASP can activate Wnt/β-catenin signaling pathway.
Fig. 4: VASP could promote translocation of β-catenin and DVL3 into the nucleus.
Fig. 5: In breast cancer, VASP was highly expressed in the nucleus, and its nuclear localization was related to the EVH1 and EVH2 domains.
Fig. 6: VASP binds to β-catenin and DVL3.
Fig. 7: In the nucleus, VASP/DVL3/β-catenin/TCF4 protein complex regulated activity of Wnt/β-catenin signaling pathway.
Fig. 8: Working model for the Wnt/β-catenin/VASP positive feedback loop in breast cancer.

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Google Scholar 

  2. Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, et al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. CA Cancer J Clin. 2016;66:43–73.

    PubMed  Google Scholar 

  3. Chen XJ, Squarr AJ, Stephan R, Chen B, Higgins TE, Barry DJ, et al. Ena/VASP proteins cooperate with the WAVE complex to regulate the actin cytoskeleton. Dev Cell. 2014;30:569–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Krause M, Bear JE, Loureiro JJ, Gertler FB. The Ena/VASP enigma. J Cell Sci. 2002;115:4721–6.

    CAS  PubMed  Google Scholar 

  5. Bruhmann S, Ushakov DS, Winterhoff M, Dickinson RB, Curth U, Faix J. Distinct VASP tetramers synergize in the processive elongation of individual actin filaments from clustered arrays. Proc Natl Acad Sci USA. 2017;114:E5815–24.

    PubMed  Google Scholar 

  6. Dertsiz L, Ozbilim G, Kayisli Y, Gokhan GA, Demircan A, Kayisli UA. Differential expression of VASP in normal lung tissue and lung adenocarcinomas. Thorax. 2005;60:576–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu Z, Wang Y, Dou C, Xu M, Sun L, Wang L, et al. Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma. Theranostics. 2018;8:4649–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang J, Zhang J, Wu J, Luo D, Su K, Shi W, et al. MicroRNA-610 inhibits the migration and invasion of gastric cancer cells by suppressing the expression of vasodilator-stimulated phosphoprotein. Eur J Cancer. 2012;48:1904–13.

    CAS  PubMed  Google Scholar 

  9. Zhang JW, Su K, Shi WT, Wang Y, Hu PC, Wang Y, et al. Matrine inhibits the adhesion and migration of BCG823 gastric cancer cells by affecting the structure and function of the vasodilator-stimulated phosphoprotein (VASP). Acta Pharmacologica Sin. 2013;34:1084–92.

    Google Scholar 

  10. Wang Y, Dong H, Zhu M, Ou Y, Zhang J, Luo H, et al. Icariin exterts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway. Eur J Pharmacol. 2010;635:40–8.

    CAS  PubMed  Google Scholar 

  11. Zhang L, Wang T, Wen X, Wei Y, Peng X, Li H, et al. Effect of matrine on HeLa cell adhesion and migration. Eur J Pharmacol. 2007;563:69–76.

    CAS  PubMed  Google Scholar 

  12. Changchun K, Pengchao H, Ke S, Ying W, Lei W. Interleukin-17 augments tumor necrosis factor alpha-mediated increase of hypoxia-inducible factor-1alpha and inhibits vasodilator-stimulated phosphoprotein expression to reduce the adhesion of breast cancer cells. Oncol Lett. 2017;13:3253–60.

    PubMed  PubMed Central  Google Scholar 

  13. Su K, Tian Y, Wang J, Shi W, Luo D, Liu J, et al. HIF-1alpha acts downstream of TNF-alpha to inhibit vasodilator-stimulated phosphoprotein expression and modulates the adhesion and proliferation of breast cancer cells. DNA Cell Biol. 2012;31:1078–87.

    CAS  PubMed  Google Scholar 

  14. Tian Y, Xu L, He Y, Xu X, Li K, Ma Y, et al. Knockdown of RAC1 and VASP gene expression inhibits breast cancer cell migration. Oncol Lett. 2018;16:2151–60.

    PubMed  PubMed Central  Google Scholar 

  15. Han G, Fan B, Zhang Y, Zhou X, Wang Y, Dong H, et al. Positive regulation of migration and invasion by vasodilator-stimulated phosphoprotein via Rac1 pathway in human breast cancer cells. Oncol Rep. 2008;20:929–39.

    CAS  PubMed  Google Scholar 

  16. Su K, Hu P, Wang X, Kuang C, Xiang Q, Yang F, et al. Tumor suppressor berberine binds VASP to inhibit cell migration in basal-like breast cancer. Oncotarget. 2016;7:45849–62.

    PubMed  PubMed Central  Google Scholar 

  17. Gkretsi V, Stylianou A, Stylianopoulos T. Vasodilator-stimulated phosphoprotein (VASP) depletion from breast cancer MDA-MB-231 cells inhibits tumor spheroid invasion through downregulation of migfilin, beta-catenin and urokinase-plasminogen activator (uPA). Exp Cell Res. 2017;352:281–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gan XQ, Wang JY, Xi Y, Wu ZL, Li YP, Li L. Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction. J Cell Biol. 2008;180:1087–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.

    CAS  PubMed  Google Scholar 

  20. Arques O, Chicote I, Puig I, Tenbaum SP, Argiles G, Dienstmann R, et al. Tankyrase inhibition blocks Wnt/beta-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin Cancer Res. 2016;22:644–56.

    CAS  PubMed  Google Scholar 

  21. Xue G, Romano E, Massi D, Mandala M. Wnt/beta-catenin signaling in melanoma: preclinical rationale and novel therapeutic insights. Cancer Treat Rev. 2016;49:1–12.

    CAS  PubMed  Google Scholar 

  22. Ma F, Ye H, He HH, Gerrin SJ, Chen S, Tanenbaum BA, et al. SOX9 drives WNT pathway activation in prostate cancer. J Clin Investig. 2016;126:1745–58.

    PubMed  Google Scholar 

  23. Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014;106:djt356.

    PubMed  Google Scholar 

  24. Wang G, Shen J, Sun J, Jiang Z, Fan J, Wang H, et al. Cyclophilin A maintains glioma-initiating cell stemness by regulating Wnt/beta-catenin signaling. Clin Cancer Res. 2017;23:6640–9.

    CAS  PubMed  Google Scholar 

  25. Liu A, Zhu J, Wu G, Cao L, Tan Z, Zhang S, et al. Antagonizing miR-455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. Mol Cancer. 2017;16:106.

    PubMed  PubMed Central  Google Scholar 

  26. Arend RC, Londono-Joshi AI, Straughn JM Jr, Buchsbaum DJ. The Wnt/beta-catenin pathway in ovarian cancer: a review. Gynecol Oncol. 2013;131:772–9.

    CAS  PubMed  Google Scholar 

  27. Wang Z, Li B, Zhou L, Yu S, Su Z, Song J, et al. Prodigiosin inhibits Wnt/beta-catenin signaling and exerts anticancer activity in breast cancer cells. Proc Natl Acad Sci USA. 2016;113:13150–5.

    CAS  PubMed  Google Scholar 

  28. Lu Y, Xie S, Zhang W, Zhang C, Gao C, Sun Q, et al. Twa1/Gid8 is a beta-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis. Cell Res. 2017;27:1422–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen Y, Li Y, Xue J, Gong A, Yu G, Zhou A, et al. Wnt-induced deubiquitination FoxM1 ensures nucleus beta-catenin transactivation. EMBO J. 2016;35:668–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang W, Li X, Lee M, Jun S, Aziz KE, Feng L, et al. FOXKs promote Wnt/beta-catenin signaling by translocating DVL into the nucleus. Dev Cell. 2015;32:707–18.

    PubMed  PubMed Central  Google Scholar 

  31. Krause M, Dent EW, Bear JE, Loureiro JJ, Gertler FB. Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration. Annu Rev Cell Dev Biol. 2003;19:541–64.

    CAS  PubMed  Google Scholar 

  32. Hansen SD, Mullins RD. Lamellipodin promotes actin assembly by clustering Ena/VASP proteins and tethering them to actin filaments. eLife. 2015;4:e06585.

  33. Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of Pygopus to the nuclear beta-catenin-TCF complex. Cell. 2002;109:47–60.

    CAS  PubMed  Google Scholar 

  34. Townsley FM, Cliffe A, Bienz M. Pygopus and legless target Armadillo/beta-catenin to the nucleus to enable its transcriptional co-activator function. Nat Cell Biol. 2004;6:626–33.

    CAS  PubMed  Google Scholar 

  35. Daniels DL, Weis WI. Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol. 2005;12:364–71.

    CAS  PubMed  Google Scholar 

  36. Hecht A, Litterst CM, Huber O, Kemler R. Functional characterization of multiple transactivating elements in beta-catenin, some of which interact with the TATA-binding protein in vitro. J Biol Chem. 1999;274:18017–25.

    CAS  PubMed  Google Scholar 

  37. Bauer A, Huber O, Kemler R. Pontin52, an interaction partner of beta-catenin, binds to the TATA box binding protein. Proc Natl Acad Sci USA. 1998;95:14787–92.

    CAS  PubMed  Google Scholar 

  38. Tago K, Nakamura T, Nishita M, Hyodo J, Nagai S, Murata Y, et al. Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev. 2000;14:1741–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Takemaru K, Yamaguchi S, Lee YS, Zhang Y, Carthew RW, Moon RT. Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway. Nature. 2003;422:905–9.

    CAS  PubMed  Google Scholar 

  40. Renfranz PJ, Beckerle MC. Doing (F/L)PPPPs: EVH1 domains and their proline-rich partners in cell polarity and migration. Curr Opin Cell Biol. 2002;14:88–103.

    CAS  PubMed  Google Scholar 

  41. Ball LJ, Kuhne R, Hoffmann B, Hafner A, Schmieder P, Volkmer-Engert R, et al. Dual epitope recognition by the VASP EVH1 domain modulates polyproline ligand specificity and binding affinity. EMBO J. 2000;19:4903–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Thorvaldsdottir H, Robinson JT, Mesirov JP. Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14:178–92.

    CAS  PubMed  Google Scholar 

  43. Sun S, Wu Y, Yu H, Su Y, Ren M, Zhu J, et al. Serum biochemistry, liver histology and transcriptome profiling of bighead carp Aristichthys nobilis following different dietary protein levels. Fish Shellfish Immunol. 2019;86:832–9.

    CAS  PubMed  Google Scholar 

  44. Grabherr MG, Haas BJ, Yassour M, Levin JZ, Thompson DA, Amit I, et al. Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nat Biotechnol. 2011;29:644–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Marioni JC, Mason CE, Mane SM, Stephens M, Gilad Y. RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays. Genome Res. 2008;18:1509–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    CAS  PubMed  Google Scholar 

  47. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res. 2008;36:D480–4.

    CAS  Google Scholar 

  48. Li K, Xu X, He Y, Tian Y, Pan W, Xu L, et al. P21-activated kinase 7 (PAK7) interacts with and activates Wnt/beta-catenin signaling pathway in breast cancer. J Cancer. 2018;9:1821–35.

    PubMed  PubMed Central  Google Scholar 

  49. Li K, Ma YB, Zhang Z, Tian YH, Xu XL, He YQ, et al. Upregulated IQUB promotes cell proliferation and migration via activating Akt/GSK3beta/beta-catenin signaling pathway in breast cancer. Cancer Med. 2018;7:3875–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Varghese F, Bukhari AB, Malhotra R, De A. IHC profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PloS ONE 2014;9:e96801.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81772823, 81572943), the Natural Science Foundation of Hubei province (2019CFA029), and Medical Science Advancement Program (Basic Medical Science) of Wuhan University (TFJC2018003).

Author information

Author notes

  1. These authors contributed equally: Kai Li, Jingwei Zhang, Yihao Tian

Authors and Affiliations

  1. Department of Pathology and Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuchang District, Wuhan, 430071, Hubei, China

    Kai Li, Yanqi He, Xiaolong Xu, Wenting Pan, Yang Gao & Lei Wei

  2. Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang, 473004, Henan, China

    Kai Li

  3. Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China

    Jingwei Zhang & Fangfang Chen

  4. Department of Anatomy, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China

    Yihao Tian

Authors
  1. Kai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingwei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yihao Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanqi He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaolong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenting Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fangfang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KL, YT, JZ, and LW designed and performed the research; YH, XX, WP, YG, and FC collected and analyzed the data; and KL, JZ, and LW analyzed the results and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lei Wei.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, K., Zhang, J., Tian, Y. et al. The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer. Oncogene 39, 2258–2274 (2020). https://doi.org/10.1038/s41388-019-1145-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-1145-3

This article is cited by

Search

Advanced search

Quick links