Skip to main content
Top
Published in: Tumor Biology 6/2011

01-12-2011 | Research Article

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

Authors: Xiao-Yun Mao, Chui-Feng Fan, Jing Wei, Cong Liu, Hua-Chuan Zheng, Fan Yao, Feng Jin

Published in: Tumor Biology | Issue 6/2011

Login to get access

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.
Literature
1.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
2.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
3.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
4.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
6.
go back to reference 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 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
7.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
8.
go back to reference 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. 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.
go back to reference Tavassoli FA. Breast pathology: rationale for adopting the ductal intraepithelial neoplasia (DIN) classification. Nat Clin Pract Oncol. 2005;2:116–7.PubMedCrossRef Tavassoli FA. Breast pathology: rationale for adopting the ductal intraepithelial neoplasia (DIN) classification. Nat Clin Pract Oncol. 2005;2:116–7.PubMedCrossRef
10.
go back to reference Tavassoli FA. Correlation between gene expression profiling-based molecular and morphologic classification of breast cancer. Int J Surg Pathol. 2010;18:167S–9S.PubMedCrossRef Tavassoli FA. Correlation between gene expression profiling-based molecular and morphologic classification of breast cancer. Int J Surg Pathol. 2010;18:167S–9S.PubMedCrossRef
11.
12.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
13.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
15.
go back to reference 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 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
16.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
17.
go back to reference Arpino G, Laucirica R, Elledge RM. Premalignant and in situ breast disease: biology and clinical implications. Ann Intern Med. 2005;143:446–57.PubMed Arpino G, Laucirica R, Elledge RM. Premalignant and in situ breast disease: biology and clinical implications. Ann Intern Med. 2005;143:446–57.PubMed
18.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
19.
go back to reference Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006;27:2355–66.PubMedCrossRef Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006;27:2355–66.PubMedCrossRef
20.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
21.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
22.
go back to reference 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 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
23.
go back to reference 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 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
24.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
27.
go back to reference Cangul H. Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet. 2004;5:27.PubMedCrossRef Cangul H. Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet. 2004;5:27.PubMedCrossRef
28.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
29.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
30.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
31.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
32.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
33.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
Metadata
Title
Increased N-myc downstream-regulated gene 1 expression is associated with breast atypia-to-carcinoma progression
Authors
Xiao-Yun Mao
Chui-Feng Fan
Jing Wei
Cong Liu
Hua-Chuan Zheng
Fan Yao
Feng Jin
Publication date
01-12-2011
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2011
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-011-0232-z

Other articles of this Issue 6/2011

Tumor Biology 6/2011 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine