Skip to main content

Advertisement

Springer Nature Link
Log in

BMX activates Wnt/β-catenin signaling pathway to promote cell proliferation and migration in breast cancer

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Breast cancer has become a dangerous killer for the female, which seriously threatened women's life, leading to huge pressures to society. The present study assessed the mechanism underlying the involvement of bone marrow tyrosine kinase on chromosome X (BMX) in breast cancer development.

Methods

The expression of BMX was examined by qPCR and immunohistochemistry. The effect of BMX on cell proliferation and migration was detected by Clone formation assay and Transwell assay. In vitro study, the correlation of BMX with Wnt/β-catenin pathway was explored by western blot and TOP/FOP flash assay.

Results

In the present study, we found that BMX was up-regulated in breast cancer, which was associated with the tumor differentiation and TNM stage. Oncogenic BMX enhanced the ability of breast cancer cell proliferation and migration. Furthermore, BMX could up-regulate the protein expression levels of p-β-catenin (Y142), p-β-catenin(Y654) and inhibit the expression level of p-β-catenin (S33/37), thus activating Wnt/β-catenin pathway in MCF-7 and MDA-MB-231 cells. In addition, we revealed that BMX promoted GSK3β phosphorylation, which suppressed the degradation of β-catenin.

Conclusions

In this study, we identified that BMX-activated Wnt/β-catenin signaling pathway, playing an oncogenic role in breast cancer, suggesting that BMX could become a potential treatment target of breast cancer.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

References

  1. Botha JL, Bray F, Sankila R, Parkin DM. Breast cancer incidence and mortality trends in 16 European countries. Eur J Cancer. 2003;39:1718–29.

    Article  CAS  Google Scholar 

  2. Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, Lee JS. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat. 2013;45:1–14.

    Article  CAS  Google Scholar 

  3. Yoshimaru T, Komatsu M, Matsuo T, Chen YA, Murakami Y, Mizuguchi K, et al. Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells. Nat Commun. 2013;4:2443.

    Article  Google Scholar 

  4. Flamini MI, Fu XD, Sanchez AM, Giretti MS, Garibaldi S, Goglia L, et al. Effects of raloxifene on breast cancer cell migration and invasion through the actin cytoskeleton. J Cell Mol Med. 2009;13:2396–407.

    Article  Google Scholar 

  5. Wang L, Liu L, Lou Z, Ding L, Guan H, Wang F, et al. Risk prediction for breast Cancer in Han Chinese women based on a cause-specific Hazard model. BMC Cancer. 2019;19:128.

    Article  Google Scholar 

  6. Weigelt B, Peterse JL, van't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.

    Article  CAS  Google Scholar 

  7. Talmadge JE. Clonal selection of metastasis within the life history of a tumor. Cancer Res. 2007;67:11471–5.

    Article  CAS  Google Scholar 

  8. Eldeeb MA, Fahlman RP. Phosphorylation impacts N-end rule degradation of the proteolytically activated form of BMX kinase. J Biol Chem. 2016;291:22757–68.

    Article  CAS  Google Scholar 

  9. Horwood NJ, Urbaniak AM, Danks L. Tec family kinases in inflammation and disease. Int Rev Immunol. 2012;31:87–103.

    Article  CAS  Google Scholar 

  10. Cenni B, Gutmann S, Gottar-Guillier M. BMX and its role in inflammation, cardiovascular disease, and cancer. Int Rev Immunol. 2012;31:166–73.

    Article  CAS  Google Scholar 

  11. van Oosterwijk JG, Buelow DR, Drenberg CD, Vasilyeva A, Li L, Shi L, et al. Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia. J Clin Invest. 2018;128:369–80.

    Article  Google Scholar 

  12. Wang Q, Zeng F, Sun Y, Qiu Q, Zhang J, Huang W, et al. Etk Interaction with PFKFB4 modulates chemoresistance of small-cell lung cancer by regulating autophagy. Clin Cancer Res. 2018;24:950–62.

    Article  CAS  Google Scholar 

  13. Potter DS, Kelly P, Denneny O, Juvin V, Stephens LR, Dive C, et al. BMX acts downstream of PI3K to promote colorectal cancer cell survival and pathway inhibition sensitizes to the BH3 mimetic ABT-737. Neoplasia. 2014;16:147–57.

    Article  CAS  Google Scholar 

  14. Guo S, Sun F, Guo Z, Li W, Alfano A, Chen H, et al. Tyrosine kinase ETK/BMX is up-regulated in bladder cancer and predicts poor prognosis in patients with cystectomy. PLoS ONE. 2011;6:e17778.

    Article  CAS  Google Scholar 

  15. Chen KY, Huang LM, Kung HJ, Ann DK, Shih HM. The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells. Oncogene. 2004;23:1854–62.

    Article  CAS  Google Scholar 

  16. Li Y, Cui N, Zheng PS, Yang WT. BMX/Etk promotes cell proliferation and tumorigenicity of cervical cancer cells through PI3K/AKT/mTOR and STAT3 pathways. Oncotarget. 2017;8:49238–52.

    PubMed  PubMed Central  Google Scholar 

  17. Shi Y, Guryanova OA, Zhou W, Liu C, Huang Z, Fang X, et al. Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance. Sci Transl Med. 2018;10:eaah6816.

    Article  Google Scholar 

  18. Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, et al. Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem Cell. 2017;21(591–603):e4.

    Google Scholar 

  19. Jaber M, Maoz M, Kancharla A, Agranovich D, Peretz T, Grisaru-Granovsky S, et al. Protease-activated-receptor-2 affects protease-activated-receptor-1-driven breast cancer. Cell Mol Life Sci. 2014;71:2517–33.

    Article  CAS  Google Scholar 

  20. Cohen I, Maoz M, Turm H, Grisaru-Granovsky S, Maly B, Uziely B, et al. Etk/Bmx regulates proteinase-activated-receptor1 (PAR1) in breast cancer invasion: signaling partners, hierarchy and physiological significance. PLoS ONE. 2010;5:e11135.

    Article  Google Scholar 

  21. Oladimeji P, Skerl R, Rusch C, Diakonova M. Synergistic activation of ERalpha by estrogen and prolactin in breast cancer cells requires tyrosyl phosphorylation of PAK1. Cancer Res. 2016;76:2600–11.

    Article  CAS  Google Scholar 

  22. 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.

    Article  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. Yang Y, Shi J, Gu Z, Salama ME, Das S, Wendlandt E, et al. Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res. 2015;75:594–604.

    Article  CAS  Google Scholar 

  25. Hamada-Kawaguchi N, Nore BF, Kuwada Y, Smith CI, Yamamoto D. Btk29A promotes Wnt4 signaling in the niche to terminate germ cell proliferation in Drosophila. Science. 2014;343:294–7.

    Article  CAS  Google Scholar 

  26. Zhou P, Li Y, Li B, Zhang M, Liu Y, Yao Y, et al. NMIIA promotes tumor growth and metastasis by activating the Wnt/beta-catenin signaling pathway and EMT in pancreatic cancer. Oncogene. 2019;38:5500–15.

    Article  CAS  Google Scholar 

  27. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.

    Article  CAS  Google Scholar 

  28. Bienz M, Clevers H. Armadillo/beta-catenin signals in the nucleus–proof beyond a reasonable doubt? Nat Cell Biol. 2003;5:179–82.

    Article  CAS  Google Scholar 

  29. Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev. 2006;16:51–9.

    Article  CAS  Google Scholar 

  30. Miravet S, Piedra J, Castano J, Raurell I, Franci C, Dunach M, et al. Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcription. Mol Cell Biol. 2003;23:7391–402.

    Article  CAS  Google Scholar 

  31. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106:1798–806.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81472765) and the Key Project of Science and Technology Department of Hubei Province (2015CFA070).

Author information

Author notes

  1. Kai Li, Wen-ting Pan and Yan-bin Ma Contributed equally.

Authors and Affiliations

  1. Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, 430071, Hubei, China

    Jing-wei Zhang

  2. Department of Pathology and Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China

    Kai Li, Wen-ting Pan, Yan-bin Ma, Xiao-long Xu, Yang Gao, Yan-qi He & Lei Wei

Authors
  1. Kai Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Wen-ting Pan
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Yan-bin Ma
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Xiao-long Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yang Gao
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Yan-qi He
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Lei Wei
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Jing-wei Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jing-wei Zhang.

Ethics declarations

Conflict of interest

All 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.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, K., Pan, Wt., Ma, Yb. et al. BMX activates Wnt/β-catenin signaling pathway to promote cell proliferation and migration in breast cancer. Breast Cancer 27, 363–371 (2020). https://doi.org/10.1007/s12282-019-01024-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-019-01024-8

Keywords