Skip to main content

Advertisement

SpringerLink
Log in

Increased N-myc downstream-regulated gene 1 expression is associated with breast atypia-to-carcinoma progression

  • Research Article
  • Published:
Tumor Biology

Abstract

N-myc downstream-regulated gene-1 (NDRG1) has been identified as a protein involved in the differentiation of epithelial cells. As a newly metastasis suppressor gene, whether it contributes to carcinogenesis of breast cancer is still unknown. This study aimed to clarify the possible role of NDRG1 for breast cancer carcinogenesis, and further to investigate its clinicopathological significance in invasive breast cancer. We examined the expression of NDRG1 in normal epithelium of breast (n = 35), usual ductal hyperplasia (n = 22), atypical ductal hyperplasia (n = 33), atypical lobular hyperplasia (n = 8), ductal carcinoma in situ (n = 16), lobular carcinoma in situ (n = 6), invasive ductal carcinoma (n = 50), and invasive lobular carcinoma (n = 45) by immunohistochemistry and analyzed the correlation between NDRG expression and clinicopathological features of invasive breast cancer. Western blot analysis was carried out to investigate the expression of NDRG1 in 20 invasive ductal breast cancer and the paired non-tumor portion of the same case. NDRG1 expression in invasive breast cancer (70/95, 73.7%) was higher than that in noninvasive breast lesions (29/85, 34.1%; p < 0.05) which was higher than that in normal breast epithelium (5/35, 14.3%; p < 0.05). Statistical analysis revealed a significant correlation between NDRG1 expression with tumor stage in invasive breast cancer, and its expression in invasive ductal carcinoma is significantly higher than invasive lobular carcinoma (p < 0.05). It was not associated with age, menopausal status, tumor size, and lymph node metastasis. NDRG1 protein levels were significantly higher in invasive ductal breast cancer compared to the paired non-tumor portion of the same case by Western blot analysis (p < 0.05). Increased NDRG-1 expression is associated with breast atypia-to-carcinoma progression. NDRG1 expression might participate in the carcinogenesis and progression of invasive breast cancer. These findings provide further evidence that NDRG1 may serve as an important biomarker for invasive 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

Similar content being viewed by others

References

  1. Chen J, Li S, Yang Z, Lu G, Hu H. Correlation between NDRG1 and PTEN expression in endometrial carcinoma. Cancer Sci. 2008;99:706–10.

    Article  PubMed  CAS  Google Scholar 

  2. Jiang K, Shen Z, Ye Y, Yang X, Wang S. A novel molecular marker for early detection and evaluating prognosis of gastric cancer: N-myc downstream regulated gene-1 (NDRG1). Scand J Gastroenterol. 2010;45:898–908.

    Article  PubMed  CAS  Google Scholar 

  3. Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, et al. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet. 2000;67:47–58.

    Article  PubMed  CAS  Google Scholar 

  4. Zhang P, Tchou-Wong KM, Costa M. Egr-1 mediates hypoxia-inducible transcription of the NDRG1 gene through an overlapping Egr-1/Sp1 binding site in the promoter. Cancer Res. 2007;67:9125–33.

    Article  PubMed  CAS  Google Scholar 

  5. Lachat P, Shaw P, Gebhard S, van Belzen N, Chaubert P, Bosman FT. Expression of NDRG1, a differentiation-related gene, in human tissues. Histochem Cell Biol. 2002;118:399–408.

    Article  PubMed  CAS  Google Scholar 

  6. Said HM, Stein S, Hagemann C, Polat B, Staab A, Anacker J, et al. Oxygen-dependent regulation of NDRG1 in human glioblastoma cells in vitro and in vivo. Oncol Rep. 2009;21:237–46.

    PubMed  CAS  Google Scholar 

  7. Ellen TP, Ke Q, Zhang P, Costa M. NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis. 2008;29:2–8.

    Article  PubMed  CAS  Google Scholar 

  8. Fan C, Yu J, Liu Y, Xu H, Wang E. Increased NDRG1 expression is associated with advanced T stages and poor vascularization in non-small cell lung cancer. Pathol Oncol Res. 2010.

  9. Tavassoli FA. Breast pathology: rationale for adopting the ductal intraepithelial neoplasia (DIN) classification. Nat Clin Pract Oncol. 2005;2:116–7.

    Article  PubMed  Google Scholar 

  10. Tavassoli FA. Correlation between gene expression profiling-based molecular and morphologic classification of breast cancer. Int J Surg Pathol. 2010;18:167S–9S.

    Article  PubMed  Google Scholar 

  11. Tavassoli FA. Lobular and ductal intraepithelial neoplasia. Pathologe. 2008;29:107–11.

    Article  PubMed  Google Scholar 

  12. Kok LF, Lee MY, Tyan YS, Wu TS, Cheng YW, Kung MF, et al. Comparing the scoring mechanisms of p16INK4a immunohistochemistry based on independent nucleic stains and independent cytoplasmic stains in distinguishing between endocervical and endometrial adenocarcinomas in a tissue microarray study. Arch Gynecol Obstet. 2010;281:293–300.

    Article  PubMed  CAS  Google Scholar 

  13. Koo CL, Kok LF, Lee MY, Wu TS, Cheng YW, Hsu JD, et al. Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. J Transl Med. 2009;7:25.

    Article  PubMed  Google Scholar 

  14. Raynaud CM, Hernandez J, Llorca FP, Nuciforo P, Mathieu MC, Commo F, et al. DNA damage repair and telomere length in normal breast, preneoplastic lesions, and invasive cancer. Am J Clin Oncol. 2010;33:341–5.

    Article  PubMed  CAS  Google Scholar 

  15. Steinman S, Wang J, Bourne P, Yang Q, Tang P. Expression of cytokeratin markers, ER-alpha, PR, HER-2/neu, and EGFR in pure ductal carcinoma in situ (DCIS) and DCIS with co-existing invasive ductal carcinoma (IDC) of the breast. Ann Clin Lab Sci. 2007;37:127–34.

    PubMed  CAS  Google Scholar 

  16. Liu T, Niu Y, Yu Y, Liu Y, Zhang F. Increased gamma-tubulin expression and P16INK4A promoter methylation occur together in preinvasive lesions and carcinomas of the breast. Ann Oncol. 2009;20:441–8.

    Article  PubMed  CAS  Google Scholar 

  17. Arpino G, Laucirica R, Elledge RM. Premalignant and in situ breast disease: biology and clinical implications. Ann Intern Med. 2005;143:446–57.

    PubMed  Google Scholar 

  18. Bai M, Agnantis NJ, Kamina S, Demou A, Zagorianakou P, Katsaraki A, et al. In vivo cell kinetics in breast carcinogenesis. Breast Cancer Res. 2001;3:276–83.

    Article  PubMed  CAS  Google Scholar 

  19. Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006;27:2355–66.

    Article  PubMed  CAS  Google Scholar 

  20. Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, et al. Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene. 2002;21:8749–58.

    Article  PubMed  CAS  Google Scholar 

  21. Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, et al. PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res. 2004;64:7655–60.

    Article  PubMed  CAS  Google Scholar 

  22. Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, et al. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 2003;63:1731–6.

    PubMed  CAS  Google Scholar 

  23. van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, et al. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms. Lab Invest. 1997;77:85–92.

    PubMed  Google Scholar 

  24. Song Y, Oda Y, Hori M, Kuroiwa K, Ono M, Hosoi F, et al. N-myc downstream regulated gene-1/Cap43 may play an important role in malignant progression of prostate cancer, in its close association with E-cadherin. Hum Pathol. 2010;41:214–22.

    Article  PubMed  CAS  Google Scholar 

  25. Chua MS, Sun H, Cheung ST, Mason V, Higgins J, Ross DT, et al. Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma. Mod Pathol. 2007;20:76–83.

    Article  PubMed  CAS  Google Scholar 

  26. Chang JT, Wang HM, Chang KW, Chen WH, Wen MC, Hsu YM, et al. Identification of differentially expressed genes in oral squamous cell carcinoma (OSCC): overexpression of NPM, CDK1 and NDRG1 and underexpression of CHES1. Int J Cancer. 2005;114:942–9.

    Article  PubMed  CAS  Google Scholar 

  27. Cangul H. Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet. 2004;5:27.

    Article  PubMed  Google Scholar 

  28. Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, et al. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene. 2004;23:5675–81.

    Article  PubMed  CAS  Google Scholar 

  29. Cangul H, Salnikow K, Yee H, Zagzag D, Commes T, Costa M. Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect. 2002;110:783–8.

    Article  PubMed  CAS  Google Scholar 

  30. Nishio S, Ushijima K, Tsuda N, Takemoto S, Kawano K, Yamaguchi T, et al. Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma. Cancer Lett. 2008;264:36–43.

    Article  PubMed  CAS  Google Scholar 

  31. Ulrix W, Swinnen JV, Heyns W, Verhoeven G. The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells. FEBS Lett. 1999;455:23–6.

    Article  PubMed  CAS  Google Scholar 

  32. Toffoli S, Delaive E, Dieu M, Feron O, Raes M, Michiels C. NDRG1 and CRK-I/II are regulators of endothelial cell migration under intermittent hypoxia. Angiogenesis. 2009;12:339–54.

    Article  PubMed  CAS  Google Scholar 

  33. Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes. J Biol Chem. 1996;271:29659–65.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 30950009).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Breast Surgery, Department of Surgical Oncology, Research Unit of General Surgery, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China

    Xiao-Yun Mao, Jing Wei, Cong Liu, Fan Yao & Feng Jin

  2. Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, 110001, China

    Chui-Feng Fan

  3. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences of China Medical University, Shenyang, 110001, China

    Hua-Chuan Zheng

Authors
  1. Xiao-Yun Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chui-Feng Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua-Chuan Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fan Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feng Jin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mao, XY., Fan, CF., Wei, J. et al. Increased N-myc downstream-regulated gene 1 expression is associated with breast atypia-to-carcinoma progression. Tumor Biol. 32, 1271–1276 (2011). https://doi.org/10.1007/s13277-011-0232-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-011-0232-z

Keywords

Search

Navigation