Skip to main content

Advertisement

SpringerLink
Log in

A study of the role of Notch1 and JAG1 gene methylation in development of breast cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

This study is to explore the roles of gene methylation of Notch1 and JAG1 in development of invasive ductal carcinoma of breast. Quantitative analysis the DNA methylation levels of Notch1 and JAG1 gene by the MassARRAY method in invasive ductal carcinoma of breast (IDC; n = 89), atypical ductal hyperplasia of breast (ADH; n = 11), and ordinary ductal hyperplasia of breast (UDH; n = 20). The expressions of JAG1 and Notch1 protein in four breast tissues were detected by immunohistochemistry SP method. (1) Positive expression rates of Notch1 protein in IDC and DCIS were 88.7 % (79/89) and 70.0 % (14/20), respectively, which were significantly higher than the levels in ADH (36.0 %, 4/11) and UDH (25.0 %, 5/20; P < 0.05). Notch1 protein expression was significant positively correlated with lymph node metastasis, pathological grades, and TNM stages of IDC. (2) Positive expression rates of JAG1 protein in IDC and DCIS were 89.9 % (80/89) and 75.0 % (15/20), respectively, which were significantly higher than those of ADH (45.0 %, 5/11) and UDH (30.0 %, 6/20; P < 0.05). JAG1 protein expression was significant positive correlation with lymph node metastasis, pathological grades and TNM stages of IDC. There is an overall hypomethylation alteration of Notch1 and JAG gene in IDC, with corresponding over-expression of Notch1 and JAG1 protein. This inverse correlation shows that the alteration of protein expression results from hypomethylation oncogene Notch1 and JAG1, and this change may play an important role in occurrence and progression 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

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
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  1. Parr C, Watkins G, Jiang WG. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumor clinicopathological parameters in human breast cancer. Int J Mol Med. 2004;14(5):779–86.

    CAS  PubMed  Google Scholar 

  2. Hao L, Rizzo P, Osipo C, et al. Notch-1 activates estrogen receptor-alpha-dependent transcription via IK Kalpha in breast cancer cells. Oncogene. 2010;29(2):201–13.

    Article  CAS  PubMed  Google Scholar 

  3. Mitsuhashi Y, Horiuchi A, Miyamoto T, et al. Prognostic significance of Notch signaling molecules and their involvement in the invasiveness of endometrial carcinoma cells. Histopathology. 2012;60(5):826–37.

    Article  PubMed  Google Scholar 

  4. Koch U, Radtke F. Notch signaling in solid tumors. Curr Top Dev Biol. 2010;92:411–55.

    Article  CAS  PubMed  Google Scholar 

  5. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.

    Article  CAS  PubMed  Google Scholar 

  6. Agrawal Anshu, Murphy RF, Agrawal DK. DNA methylation in breast and colorectal cancers. Mod Pathol. 2007;20(7):711–21.

    Article  CAS  PubMed  Google Scholar 

  7. Itoh H, Lwasaki M, Kasuga Y, et al. Association between serum organochlorines and global methylation level of leukocyte DNA among Japanese women: a cross-sectional study. Sci Total Environ. 2014;490(15):603–9.

    Article  CAS  PubMed  Google Scholar 

  8. Siegel R, Ma J, Jemal A. Cancer statistics 2014. CA Cancer J Clin. 2014;64(1):9–29.

    Article  PubMed  Google Scholar 

  9. Han J, Hendzel MJ, Allalunis TJ. Notch signaling as a therapeutic target for breast cancer treatment? Breast Cancer Res. 2011;13(3):210–6.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jonusiene V, Sasnauskiene A, Lachei N, et al. Down-regulated expression of Notch signaling molecules in human endometrial cancer. Med Oncol. 2013;30(1):438–45.

    Article  PubMed  Google Scholar 

  11. Wael H, Yoshida R, Kudoh S, et al. Notch1 signaling controls cell proliferation, apoptosis and differentiation in lung carcinoma. Lung Cancer. 2014;13(5):210–4.

    Google Scholar 

  12. Dominguez M. Oncogenic programmes and Notch activity: an ‘organized crime’? Semin Cell Dev Biol. 2014;28(4):78–85.

    Article  CAS  PubMed  Google Scholar 

  13. Zardwi SJ, Zardawi I, McNeil CM, et al. High Notch1 protein expression is an early event in breast cancer development and is associated with the HER-2 molecular subtype. Histopathology. 2010;56(3):286–96.

    Article  Google Scholar 

  14. Reedijk M, Odorcic S, Chang L, et al. High-level coexpression of JAG1 and notch1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 2005;65:8530–7.

    Article  CAS  PubMed  Google Scholar 

  15. Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54(5):716–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ellis L, Atadja PW, Johnstone RW. Epigeneties in cancer: targeting chromatin modifications. Mol Cancer Ther. 2009;8(6):1409–20.

    Article  CAS  PubMed  Google Scholar 

  17. Haller F, Moskalev EA, Faucz FR, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014;21(4):567–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gautrey HE, van Otterdijk SD, Cordell HJ, et al. DNA methylation abnormalities at gene promoters are extensive and variable in the elderly and phenocopy cancer cells. FASEB J. 2014;28(7):3261–72.

    Article  CAS  PubMed  Google Scholar 

  19. Avraham Ayelet, Cho Sean Soonweng, Uhlmann Ronit, et al. Tissue specific DNA methylation in normal human breast epithelium and in breast cancer. PLoS One. 2014;9(3):1–8.

    Article  Google Scholar 

  20. Tokaraz P, Blasiak J. Role of DNA methylation in colorectal cancer. Postepy Biochem. 2013;59(3):267–79.

    Google Scholar 

  21. Aran D, Sabato S, Hellman A. DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes. Genome Biol. 2013;14(3):2–4.

    Article  Google Scholar 

  22. Fukushige S, Horii A. DNA methylation in cancer: a gene silencing mechanism and the clinical potential of its biomarkers. Tohoku J Exp Med. 2013;229(3):173–85.

    Article  CAS  PubMed  Google Scholar 

  23. Sharma G, Mirza S, Parshad R, et al. CpG hypomethylation of MDR1 gene in tumor and serum of invasive ductal breast carcinoma patients[J]. Clin Biochem. 2010;43(4–5):373–9.

    Article  CAS  PubMed  Google Scholar 

  24. Fujita N, Kagara N, Yamamoto N, et al. Methylated DNA and high total DNA levels in the serum of patients with breast cancer following neoadjuvant chemotherapy are predictive of a poor prognosis. Oncol Lett. 2014;8(1):397–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Rao X, Evans J, Chae H, et al. CpG island shore methylation regulates caveolin-1 expression in breast cancer. Oncogene. 2013;32(38):4519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jiao F, Bai SY, Ma Y, et al. DNA methylation of heparanase promoter influences its expression and associated with the progression of human breast cancer. PLoS One. 2014;9(3):1–12.

    Google Scholar 

  27. Heyn H, Sayols S, Moutinho C, et al. Linkage of DNA methylation quantitative trait loci to human cancer risk. Cell Rep. 2014;7(2):331–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430071, Hubei Province, People’s Republic of China

    Huapeng Sun & Shiqiang Shen

  2. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei Province, People’s Republic of China

    Kun Li

Authors
  1. Huapeng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiqiang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiqiang Shen.

Ethics declarations

Conflicts of interest

We declare that we have no financial or commercial conflicts of interest pertaining to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, H., Li, K. & Shen, S. A study of the role of Notch1 and JAG1 gene methylation in development of breast cancer. Med Oncol 33, 35 (2016). https://doi.org/10.1007/s12032-016-0750-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-016-0750-z

Keywords

Search

Navigation