Skip to main content

Advertisement

SpringerLink
Log in

The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells

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

Abstract

Background

Epidermal growth factor receptor (EGFR) is often overexpressed in triple-negative breast cancer (TNBC). However, clinical studies have shown that therapies against EGFR are not effective in patients with TNBC. Recently, it has been reported that arginine 198/200 in EGFR extracellular domain is methylated by PRMT1 and that the methylation confers resistance to EGFR monoclonal antibody cetuximab in colorectal cancer cells. To explore a potential mechanism underlying intrinsic resistance to anti-EGFR therapy in TNBC, we investigated the role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 (468) TNBC cells.

Methods

We knocked down PRMT1 in 468 cells by shRNA, and subjected the cell lysates to Western blot analysis to examine EGFR activation and its downstream molecules. We also evaluated cell proliferation and sphere formation of PRMT1-knockdown cells. Finally, we examined the effects of pan-PRMT inhibitor, AMI-1, on cetuximab by colony formation and soft agar assays.

Results

EGFR methylation and activity was significantly reduced in PRMT1-knockdown cells compared to the parental cells. Knockdown of PRMT1 also reduced cell proliferation and sphere formation. Moreover, AMI-1 sensitized 468 cells to cetuximab.

Conclusion

The results indicate that PRMT1 is critical for EGFR activity in 468 cells. Our data also suggest that inhibition of PRMT1 sensitizes TNBC cells to cetuximab. Thus, inhibition of PRMT1 may be an effective therapeutic strategy to overcome intrinsic resistance to cetuximab in TNBC.

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

Access this article

Log in via an institution

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. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.

    Article  CAS  PubMed  Google Scholar 

  2. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.

    Article  PubMed  Google Scholar 

  3. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3–8.

    Article  CAS  PubMed  Google Scholar 

  4. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:15–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012;136:331–45.

    Article  CAS  PubMed  Google Scholar 

  6. Nakai K, Hung MC, Yamaguchi H. A perspective on anti-EGFR therapies targeting triple-negative breast cancer. Am J Cancer Res. 2016;6:1609–23.

    PubMed  PubMed Central  Google Scholar 

  7. Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012;30:2615–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baselga J, Gomez P, Greil R, Braga S, Climent MA, Wardley AM, et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2013;31:2586–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13:37–50.

    Article  CAS  PubMed  Google Scholar 

  10. Wang L, Zhao Z, Meyer MB, Saha S, Yu M, Guo A, et al. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell. 2014;25:21–36.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Baldwin RM, Morettin A, Paris G, Goulet I, Cote J. Alternatively spliced protein arginine methyltransferase 1 isoform PRMT1v2 promotes the survival and invasiveness of breast cancer cells. Cell Cycle. 2012;11:4597–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD, et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science. 2001;293:853–7.

    Article  CAS  PubMed  Google Scholar 

  13. Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell. 2008;32:221–31.

    Article  CAS  PubMed  Google Scholar 

  14. Le Romancer M, Treilleux I, Leconte N, Robin-Lespinasse Y, Sentis S, Bouchekioua-Bouzaghou K, et al. Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Mol Cell. 2008;31:212–21.

    Article  PubMed  Google Scholar 

  15. Boisvert FM, Dery U, Masson JY, Richard S. Arginine methylation of MRE11 by PRMT1 is required for DNA damage checkpoint control. Genes Dev. 2005;19:671–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Boisvert FM, Rhie A, Richard S, Doherty AJ. The GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity. Cell Cycle. 2005;4:1834–41.

    Article  CAS  PubMed  Google Scholar 

  17. Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, et al. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol. 2011;13:174–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liao HW, Hsu JM, Xia W, Wang HL, Wang YN, Chang WC, et al. PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. J Clin Invest. 2015;125:4529–43.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Moasser MM, Basso A, Averbuch SD, Rosen N. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 2001;61:7184–8.

    CAS  PubMed  Google Scholar 

  21. Farnie G, Clarke RB, Spence K, Pinnock N, Brennan K, Anderson NG, et al. Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst. 2007;99:616–27.

    Article  CAS  PubMed  Google Scholar 

  22. Walport LJ, Hopkinson RJ, Chowdhury R, Schiller R, Ge W, Kawamura A, et al. Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases. Nat Commun. 2016;7:11974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(−) stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thakur R, Trivedi R, Rastogi N, Singh M, Mishra DP. Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep. 2015;5:10194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bae GY, Choi SJ, Lee JS, Jo J, Lee J, Kim J, et al. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013;4:2512–22.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Peddi PF, Ellis MJ, Ma C. Molecular basis of triple negative breast cancer and implications for therapy. Int J Breast Cancer. 2012;2012:217185.

    Article  PubMed  Google Scholar 

  27. Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:918–27.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded in part by the Cancer Prevention and Research Institute of Texas (RP150245).

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA

    Katsuya Nakai, Weiya Xia, Hsin-Wei Liao, Mien-Chie Hung & Hirohito Yamaguchi

  2. Department of Breast Oncology, Juntendo University School of Medicine, Hongo 2-1-1, Bunyo-ku, Tokyo, 113-0033, Japan

    Katsuya Nakai & Mitsue Saito

Authors
  1. Katsuya Nakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weiya Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hsin-Wei Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mitsue Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mien-Chie Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hirohito Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Katsuya Nakai or Hirohito Yamaguchi.

Ethics declarations

Conflict of interest

There is no conflict of interest to declare.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakai, K., Xia, W., Liao, HW. et al. The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells. Breast Cancer 25, 74–80 (2018). https://doi.org/10.1007/s12282-017-0790-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-017-0790-z

Keywords

Search

Navigation