Chromodomain helicase DNA binding protein 5 plays a tumor suppressor role in human breast cancer

• Type of Material: Article
• Authors: Xiao Wu, Nankai University; Zhengmao Zhu, Nankai University; Weidong Li, Tianjin Medical University; Xiaoying Fu, Emory University; Dan Su, Nankai University; Liya Fu, Nankai University; Zhiqian Zhang, Nankai University; Ang Luo, Nankai University; Xiaodong Sun, Emory University; Li Fu, Tianjin Medical University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2012-05-08
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Wu et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://breast-cancer-research.com/content/14/3/R73
• Title of Journal or Parent Work: Breast Cancer Research
• ISSN: 1465-5411
• Volume: 14
• Issue: R73
• Start Page: 1
• End Page: 16
• Grant/Funding Information: This work was supported by grants from the National Natural Science Foundation of China (30870980, 30625032, and 30930038), Doctoral Fund of Ministry of Education of China (200800551032), the National Key Scientific Program of China (2007CB914802), and the Major Projects of National Science and Technology (2009ZX08009-151B).
• Research Categories: Health Sciences, Oncology

Abstract

Introduction The chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model. The CHD5 locus at 1p36 is deleted, and its mutation has been detected in breast cancer. We, therefore, evaluated whether CHD5 plays a role in human breast cancer. Methods We screened mutations in 55 tumors, determined promoter methylation in 39 tumors, measured RNA expression in 90 tumors, analyzed protein expression in 289 tumors, and correlated expression changes with clinicopathological characteristics of breast cancer. Functional effects of CHD5 on cell proliferation, invasion and tumorigenesis were also tested. Results Although only one mutation was detected, CHD5 mRNA expression was significantly reduced, accompanied by frequent genomic deletion and promoter methylation, in breast cancer. The extent of methylation was significantly associated with reduced mRNA expression, and demethylating treatment restored CHD5 expression. Lower CHD5 mRNA levels correlated with lymph node metastasis (P = 0.026). CHD5 protein expression was also reduced in breast cancer, and lack of CHD5 expression significantly correlated with higher tumor stage, ER/PR-negativity, HER2 positivity, distant metastasis and worse patient survival (P ≤ 0.01). Functionally, ectopic expression of CHD5 in breast cancer cells inhibited cell proliferation and invasion in vitro and tumorigenesis in nude mice. Consistent with the inhibition of invasion, CHD5 down-regulated mesenchymal markers vimentin, N-cadherin and ZEB1 in breast cancer cells. Conclusion Down-regulation of CHD5, mediated at least in part by promoter methylation, contributes to the development and progression of human breast cancer.