Pathology & Oncology Research

, Volume 25, Issue 1, pp 71–79 | Cite as

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

  • Yuandong Wang
  • Yan Zhang
  • Qian Lu
  • Yiming Wang
  • Xinchen Sun
  • Shu ZhangEmail author
Original Article


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.


Serum DJ-1 HER3 NRG-1 Breast cancers MCF-7 cells 



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).

Compliance with Ethical Standards

Conflict of Interest

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


  1. 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. CrossRefGoogle Scholar
  2. 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. CrossRefGoogle Scholar
  3. 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. CrossRefGoogle Scholar
  4. 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. CrossRefGoogle Scholar
  5. 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. CrossRefGoogle Scholar
  6. 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. CrossRefGoogle Scholar
  7. 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. CrossRefGoogle Scholar
  8. 8.
    Karagianni M, Kaitelidou D, Kalokairinou A, Mantas J (2014) Breast cancer in social media: a literature review. Stud Health Technol Inform 202:321Google Scholar
  9. 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 7:3328–3335Google Scholar
  10. 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. CrossRefGoogle Scholar
  11. 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. CrossRefGoogle Scholar
  12. 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. CrossRefGoogle Scholar
  13. 13.
    Mujoo K, Choi BK, Huang Z, Zhang N, An Z (2014) Regulation of ERBB3/HER3 signaling in cancer. Oncotarget 5:10222–10236. CrossRefGoogle Scholar
  14. 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. CrossRefGoogle Scholar
  15. 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. CrossRefGoogle Scholar
  16. 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. CrossRefGoogle Scholar
  17. 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. CrossRefGoogle Scholar
  18. 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. CrossRefGoogle Scholar
  19. 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. Google Scholar
  20. 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 14:3550–3558CrossRefGoogle Scholar
  21. 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. CrossRefGoogle Scholar
  22. 22.
    Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360:790–800. CrossRefGoogle Scholar
  23. 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. CrossRefGoogle Scholar
  24. 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. CrossRefGoogle Scholar
  25. 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. Google Scholar
  26. 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. Google Scholar
  27. 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. CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  1. 1.Department of RadiotherapyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of Anesthesiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  3. 3.School of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyAustralia
  4. 4.Department of Radiotherapy, Clinical Research CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China

Personalised recommendations