Skip to main content

Advertisement

Log in

NRG-1 Stimulates Serum DJ-1 Increase in Breast Cancers

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

To explore the relationship between the expression of DJ-1/HER3 and tumor grade in breast cancer, and investigate the effect of HER3 on NRG-1-mediated serum DJ-1 level in vivo. We analyze the expression level of DJ-1 and HER3 in 68 patients with different grades of breast cancer by immunostaining the tissue microarray. Besides, we investigated the serum DJ-1 level by ELISA. We found that the detectable DJ-1 protein expression is decreased, and the HER3 expression is increased in tumor tissue with the progression of breast cancer. There is a significant rise of DJ-1 in serum in vivo with the stimulation of NRG-1. Meanwhile, we found that HER3 knockdown abolishes NRG-1-induced serum DJ-1 increase and HER3 overexpress improves NRG-1-induced serum DJ-1 increase. This study provides a serum biomarker for breast cancer. The results showed that DJ-1 was associated with clinical stage of breast cancer, and NRG-1 increased the dissociation of HER3 and DJ-1, with promoting the level of DJ-1 in peripheral blood. It is suggested that the level of DJ-1 in peripheral blood may be conducive to assess the prognosis of patients with breast cancer and serum DJ-1 levels can serve as an indicator of therapeutic effectiveness for the development of HER3 targeting breast cancer antibody therapies.

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

Access this article

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. Allard L, Burkhard PR, Lescuyer P, Burgess JA, Walter N, Hochstrasser DF, Sanchez JC (2005) PARK7 and nucleoside diphosphate kinase A as plasma markers for the early diagnosis of stroke. Clin Chem 51:2043–2051. https://doi.org/10.1373/clinchem.2005.053942

    Article  CAS  PubMed  Google Scholar 

  2. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259. https://doi.org/10.1126/science.1077209

    Article  CAS  Google Scholar 

  3. Brenton JD, Carey LA, Ahmed AA, Caldas C (2005) Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 23:7350–7360. https://doi.org/10.1200/JCO.2005.03.3845

    Article  CAS  PubMed  Google Scholar 

  4. Choi BK, Cai X, Yuan B, Huang Z, Fan X, Deng H, Zhang N, An Z (2012) HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways. Protein Cell 3:781–789. https://doi.org/10.1007/s13238-012-2065-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chung C, Lee S, Hwang S, Park E (2013) Systematic review of exercise effects on health outcomes in women with breast cancer. Asian Nurs Res (Korean Soc Nurs Sci) 7:149–159. https://doi.org/10.1016/j.anr.2013.07.005

    Article  Google Scholar 

  6. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043. https://doi.org/10.1126/science.1141478

    Article  CAS  PubMed  Google Scholar 

  7. Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, Inagaki F (2003) The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. J Biol Chem 278:31380–31384. https://doi.org/10.1074/jbc.M305878200

    Article  CAS  PubMed  Google Scholar 

  8. Karagianni M, Kaitelidou D, Kalokairinou A, Mantas J (2014) Breast cancer in social media: a literature review. Stud Health Technol Inform 202:321

    PubMed  Google Scholar 

  9. Le Naour F, Misek DE, Krause MC, Deneux L, Giordano TJ, Scholl S, Hanash SM (2001) Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer. Clin Cancer Res 7:3328–3335

    PubMed  Google Scholar 

  10. Mahar I, Tan S, Davoli MA, Dominguez-Lopez S, Qiang C, Rachalski A, Turecki G, Mechawar N (2011) Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects. PLoS One 6:e26610. https://doi.org/10.1371/journal.pone.0026610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maita C, Tsuji S, Yabe I, Hamada S, Ogata A, Maita H, Iguchi-Ariga SM, Sasaki H, Ariga H (2008) Secretion of DJ-1 into the serum of patients with Parkinson's disease. Neurosci Lett 431:86–89. https://doi.org/10.1016/j.neulet.2007.11.027

    Article  CAS  PubMed  Google Scholar 

  12. Meetze K, Vincent S, Tyler S, Mazsa EK, Delpero AR, Bottega S, McIntosh D, Nicoletti R, Winston WM, Weiler S, Feng B, Gyuris J, Weng Z (2015) Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models. Clin Cancer Res 21:1106–1114. https://doi.org/10.1158/1078-0432.CCR-14-2407

    Article  CAS  PubMed  Google Scholar 

  13. Mujoo K, Choi BK, Huang Z, Zhang N, An Z (2014) Regulation of ERBB3/HER3 signaling in cancer. Oncotarget 5:10222–10236. https://doi.org/10.18632/oncotarget.2655

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H (1997) DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 231:509–513. https://doi.org/10.1006/bbrc.1997.6132

    Article  CAS  Google Scholar 

  15. Oda M, Makita M, Iwaya K, Akiyama F, Kohno N, Tsuchiya B, Iwase T, Matsubara O (2012) High levels of DJ-1 protein in nipple fluid of patients with breast cancer. Cancer Sci 103:1172–1176. https://doi.org/10.1111/j.1349-7006.2012.02267.x

    Article  CAS  PubMed  Google Scholar 

  16. Pardo M, Garcia A, Thomas B, Pineiro A, Akoulitchev A, Dwek RA, Zitzmann N (2006) The characterization of the invasion phenotype of uveal melanoma tumour cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker. Int J Cancer 119:1014–1022. https://doi.org/10.1002/ijc.21942

    Article  CAS  PubMed  Google Scholar 

  17. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441. https://doi.org/10.1038/nature05474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shames DS, Carbon J, Walter K, Jubb AM, Kozlowski C, Januario T, Do A, Fu L, Xiao Y, Raja R, Jiang B, Malekafzali A, Stern H, Settleman J, Wilson TR, Hampton GM, Yauch RL, Pirzkall A, Amler LC (2013) High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck. PLoS One 8:e56765. https://doi.org/10.1371/journal.pone.0056765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sobin LH, Compton CC (2010) TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer-Am Cancer Soc 116:5336–5339. https://doi.org/10.1002/cncr.25537

    Article  Google Scholar 

  20. Soltoff SP, Carraway KR, Prigent SA, Gullick WG, Cantley LC (1994) ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 14:3550–3558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423. https://doi.org/10.1073/pnas.0932692100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360:790–800. https://doi.org/10.1056/NEJMra0801289

    Article  CAS  PubMed  Google Scholar 

  23. Tsuboi Y, Munemoto H, Ishikawa S, Matsumoto K, Iguchi-Ariga SM, Ariga H (2008) DJ-1, a causative gene product of a familial form of Parkinson's disease, is secreted through microdomains. FEBS Lett 582:2643–2649. https://doi.org/10.1016/j.febslet.2008.06.043

    Article  CAS  PubMed  Google Scholar 

  24. Tsuchiya B, Iwaya K, Kohno N, Kawate T, Akahoshi T, Matsubara O, Mukai K (2012) Clinical significance of DJ-1 as a secretory molecule: retrospective study of DJ-1 expression at mRNA and protein levels in ductal carcinoma of the breast. Histopathology 61:69–77. https://doi.org/10.1111/j.1365-2559.2012.04202.x

    Article  PubMed  Google Scholar 

  25. Zhang N, Chang Y, Rios A, An Z (2016) HER3/ErbB3, an emerging cancer therapeutic target. Acta Biochim Biophys Sin Shanghai 48:39–48. https://doi.org/10.1093/abbs/gmv103

    Article  CAS  PubMed  Google Scholar 

  26. Zhang S, Mukherjee S, Fan X, Salameh A, Mujoo K, Huang Z, Li L, To'A SG, Zhang N, An Z (2016) Novel association of DJ-1 with HER3 potentiates HER3 activation and signaling in cancer. Oncotarget 7:65758–65769. https://doi.org/10.18632/oncotarget.11613

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL (2006) The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J Mol Biol 356:1036–1048. https://doi.org/10.1016/j.jmb.2005.12.030

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This project was sponsored by the National Natural Science Foundation of China (No. 81373398); a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shu Zhang.

Ethics declarations

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Zhang, Y., Lu, Q. et al. NRG-1 Stimulates Serum DJ-1 Increase in Breast Cancers. Pathol. Oncol. Res. 25, 71–79 (2019). https://doi.org/10.1007/s12253-017-0326-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0326-z

Keywords

Navigation