Skip to main content

Advertisement

SpringerLink
Log in

A novel ADC targeting cell surface fibromodulin in a mouse model of triple-negative breast cancer

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

Abstract

Background

Triple-negative breast cancers (TNBCs) are highly aggressive and metastatic. To date, finding efficacious targeted therapy molecules might be the only window of hope to cure cancer. Fibromodulin (FMOD), is ectopically highly expressed on the surface of Chronic Lymphocytic Leukemia (CLL) and bladder carcinoma cells; thus, it could be a promising molecule for targeted therapy of cancer. The objective of this study was to evaluate cell surface expression of FMOD in two TNBC cell lines and develop an antibody–drug conjugate (ADC) to target FMOD positive TNBC in vitro and in vivo.

Materials and methods

Two TNBC-derived cell lines 4T1 and MDA-MB-231 were used in this study. The specific binding of anti-FMOD monoclonal antibody (mAb) was evaluated by flow cytometry and its internalization was verified using phAb amine reactive dye. A microtubulin inhibitor Mertansine (DM1) was used for conjugation to anti-FMOD mAb. The binding efficacy of FMOD-ADC was assessed by immunocytochemistry technique. The anti-FMOD mAb and FMOD-ADC apoptosis induction were measured using Annexin V-FITC and flow cytometry. Tumor growth inhibition of anti-FMOD mAb and FMOD-ADC was evaluated using BALB/c mice injected with 4T1 cells.

Results

Our results indicate that both anti-FMOD mAb and FMOD-ADC recognize cell surface FMOD molecules. FMOD-ADC could induce apoptosis in 4T1 and MDA-MB-231 cells in vitro. In vivo tumor growth inhibition was observed using FMOD-ADC in 4T1 inoculated BALB/c mice.

Conclusion

Our results suggests high cell surface FMOD expression could be a novel bio-marker TNBCs. Furthermore, FMOD-ADC could be a promising candidate for targeting TNBCs.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Mattiuzzi C, Lippi G. Current cancer epidemiology. J Epidemiol Glob Health. 2019;9(4):217.

    Article  Google Scholar 

  2. Weir HK, Thompson TD, Soman A, Møller B, Leadbetter S. The past, present, and future of cancer incidence in the United States: 1975 through 2020. Cancer. 2015;121(11):1827–37.

    Article  Google Scholar 

  3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2021;71(3):209–49.

    Article  Google Scholar 

  4. Si Y, Xu Y, Guan J, Chen K, Kim S, Yang ES, et al. Anti-EGFR antibody-drug conjugate for triple-negative breast cancer therapy. Eng Life Sci. 2021;21(1–2):37–44.

    Article  CAS  Google Scholar 

  5. Esteva FJ, Hubbard-Lucey VM, Tang J, Pusztai L. Immunotherapy and targeted therapy combinations in metastatic breast cancer. Lancet Oncol. 2019;20(3):e175–86.

    Article  CAS  Google Scholar 

  6. Kimiz-Gebologlu I, Gulce-Iz S, Biray-Avci C. Monoclonal antibodies in cancer immunotherapy. Mol Biol Rep. 2018;45(6):2935–40.

    Article  CAS  Google Scholar 

  7. Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC. Monoclonal antibody successes in the clinic. Nat Biotechnol. 2005;23(9):1073–8.

    Article  CAS  Google Scholar 

  8. Zahavi D, Weiner L. Monoclonal antibodies in cancer therapy. Antibodies. 2020;9(3):34.

    Article  CAS  Google Scholar 

  9. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98–107.

    Article  CAS  Google Scholar 

  10. Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody–drug conjugates: a comprehensive review. Mol Cancer Res. 2020;18(1):3–19.

    Article  CAS  Google Scholar 

  11. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91.

    Article  CAS  Google Scholar 

  12. Congreve S, Faris Elias R, Tidestav G, Zafranian v. Antibody drug conjugates (ADC): current status and mapping of ADC: s in clinical programs, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-352917

  13. Spring LM, Nakajima E, Hutchinson J, Viscosi E, Blouin G, Weekes C, et al. Sacituzumab govitecan for metastatic triple-negative breast cancer: clinical overview and management of potential toxicities. Oncologist. 2021;26(10):827–34.

    Article  CAS  Google Scholar 

  14. Wahby S, Fashoyin-Aje L, Osgood CL, Cheng J, Fiero MH, Zhang L, et al. FDA approval summary: accelerated approval of sacituzumab govitecan-hziy for third-line treatment of metastatic triple-negative breast cancer. Clin Cancer Res. 2021;27(7):1850–4.

    Article  CAS  Google Scholar 

  15. Romero D. Benefit in patients with PD-L1-positive TNBC. Nat Rev Clin Oncol. 2019;16(1):6–6.

    PubMed  Google Scholar 

  16. Zent R, Pozzi A. Cell-extracellular matrix interactions in cancer. Berlin: Springer; 2010.

    Book  Google Scholar 

  17. Krishnan L, Hoying JB, Nguyen H, Song H, Weiss JA. Interaction of angiogenic microvessels with the extracellular matrix. Am J Physiol-Heart Circ Physiol. 2007;293(6):H3650–8.

    Article  CAS  Google Scholar 

  18. Naito Z. The role of small leucine-rich proteoglycan (SLRP) family in pathological lesions and cancer cell growth. J Nippon Med Sch. 2005;72(3):137–45.

    Article  CAS  Google Scholar 

  19. Iozzo RV, Schaefer L. Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J. 2010;277(19):3864–75.

    Article  CAS  Google Scholar 

  20. Soo C, Hu F-Y, Zhang X, Wang Y, Beanes SR, Lorenz HP, et al. Differential expression of fibromodulin, a transforming growth factor-β modulator, in fetal skin development and scarless repair. Am J Pathol. 2000;157(2):423–33.

    Article  CAS  Google Scholar 

  21. Lee Y-H, Schiemann WP. Fibromodulin suppresses nuclear factor-κb activity by inducing the delayed degradation of IKBA via a JNK-dependent pathway coupled to fibroblast apoptosis. J Biol Chem. 2011;286(8):6414–22.

    Article  CAS  Google Scholar 

  22. DawoodyNejad L, Biglari A, Annese T, Ribatti D. Recombinant fibromodulin and decorin effects on NF-κB and TGFβ1 in the 4T1 breast cancer cell line. Oncol Lett. 2017;13(6):4475–80.

    Article  Google Scholar 

  23. Bettin A, Reyes I, Reyes N. Gene expression profiling of prostate cancer-associated genes identifies fibromodulin as potential novel biomarker for prostate cancer. Int J Biol Markers. 2016;31(2):153–62.

    Article  Google Scholar 

  24. Reyes N, Benedetti I, Bettin A, Rebollo J, Geliebter J. The small leucine rich proteoglycan fibromodulin is overexpressed in human prostate epithelial cancer cell lines in culture and human prostate cancer tissue. Cancer Biomark. 2016;16(1):191–202.

    Article  CAS  Google Scholar 

  25. Colin C, Baeza N, Bartoli C, Fina F, Eudes N, Nanni I, et al. Identification of genes differentially expressed in glioblastoma versus pilocytic astrocytoma using Suppression Subtractive Hybridization. Oncogene. 2006;25(19):2818–26.

    Article  CAS  Google Scholar 

  26. Farahi L, Ghaemimanesh F, Milani S, Razavi SM, Hadavi R, Bayat AA, et al. GPI-anchored fibromodulin as a novel target in chronic lymphocytic leukemia: diagnostic and therapeutic implications. Iran J Immunol. 2019;16(2):127–41.

    PubMed  Google Scholar 

  27. Bayat A-A, Sadeghi N, Salimi A, Fazli G, Nowroozi MR, Moghadam SO, et al. The association of cell surface fibromodulin expression and bladder carcinoma. Urol J. 2021. https://doi.org/10.22037/uj.v18i.6461.

    Article  PubMed  Google Scholar 

  28. Choudhury A, Derkow K, Daneshmanesh AH, Mikaelsson E, Kiaii S, Kokhaei P, et al. Silencing of ROR1 and FMOD with siRNA results in apoptosis of CLL cells. Br J Haematol. 2010;151(4):327–35.

    Article  CAS  Google Scholar 

  29. Riggio AI, Varley KE, Welm AL. The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer. 2020;124:1–14.

    Google Scholar 

  30. Bi X-L, Yang W. Biological functions of decorin in cancer. Chin J Cancer. 2013;32(5):266.

    Article  CAS  Google Scholar 

  31. Pourhanifeh MH, Mohammadi R, Noruzi S, Hosseini SA, Fanoudi S, Mohamadi Y, et al. The role of fibromodulin in cancer pathogenesis: implications for diagnosis and therapy. Cancer Cell Int. 2019;19(1):1–9.

    Article  Google Scholar 

  32. Mikaelsson E, et al. Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Blood. 2005;105(12):4828-4835.

  33. DeNardo SJ. Radioimmunodetection and therapy of breast cancer. In: Seminars in nuclear medicine. Amsterdam: Elsevier; 2005.

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Avicenna Research Institute, ACECR, Tehran, Iran (Grant No. 960205-012) and Tehran University of Medical Sciences, Tehran, Iran (Grant No. 97-03-87-40182).

Author information

Authors and Affiliations

  1. Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mozhan Haji Ghaffari & Mohammadali Mazloomi

  2. Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

    Miganoosh Simonian, Ali Salimi, Niloufar Sadeghi, Mohammad-Reza Nejadmoghaddam, Nasim Ebrahimnezhad, Ghazaleh Fazli, Ramina Fatemi, Ali-Ahmad Bayat & Hodjattallah Rabbani

  3. Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

    Ebrahim Mirzadegan

Authors
  1. Mozhan Haji Ghaffari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miganoosh Simonian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ali Salimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ebrahim Mirzadegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Niloufar Sadeghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad-Reza Nejadmoghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nasim Ebrahimnezhad
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ghazaleh Fazli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ramina Fatemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ali-Ahmad Bayat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mohammadali Mazloomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hodjattallah Rabbani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammadali Mazloomi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the ethics committee of Tehran University of Medical Sciences. (Approval number: IR.TUMS.VCR.REC.1397.1079).

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

Haji Ghaffari, M., Simonian, M., Salimi, A. et al. A novel ADC targeting cell surface fibromodulin in a mouse model of triple-negative breast cancer. Breast Cancer 29, 1121–1132 (2022). https://doi.org/10.1007/s12282-022-01393-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-022-01393-7

Keywords

Search

Navigation