Epigenetic silencing of HOPX contributes to cancer aggressiveness in breast cancer

• Published in: Cancer letters 2017-01, Vol.384, p.70-78
• Main Authors: Kikuchi, Mariko, Katoh, Hiroshi, Waraya, Mina, Tanaka, Yoko, Ishii, Satoru, Tanaka, Toshimichi, Nishizawa, Nobuyuki, Yokoi, Keigo, Minatani, Naoko, Ema, Akira, Kosaka, Yoshimasa, Tanino, Hirokazu, Yamashita, Keishi, Watanabe, Masahiko
• Format: Article
• Language: English
• Subjects: Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation; Conflicts of interest; DNA Methylation; Epigenesis, Genetic; Epigenetic silencing; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes; Hematology, Oncology and Palliative Medicine; HER2; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; HOPX; Humans; Lymphatic Metastasis; MCF-7 Cells; Mortality; Neoplasm Invasiveness; Phenotype; Prognosis; Promoter Regions, Genetic; Receptor, ErbB-2 - metabolism; Time Factors; Transfection; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2016.10.017

Abstract Epigenetic silencing of HOPX has been shown frequent and specific in human cancers. HOPX is thought as a tumor suppressor gene and its promoter methylation is the main mechanism of down-regulation. In non-hereditary breast cancer, since roles of epigenetic modifications are more critical than in other cancers, the aim of this study is to seek into the roles and clinical relevance of epigenetic silencing of HOPX. Down-regulation of HOPX was observed in all human breast cancer cell lines tested. The promoter methylation was found in six of seven cell lines, and demethylating agents restored HOPX expression. The promoter methylation was cancer-specific in human breast tissues. Forced expression of HOPX attenuated anchorage-independent growth in vitro. HOPX promoter methylation independently predicted worse prognosis of breast cancer patients. Of note, HOPX promoter methylation was significantly associated with HER2 positivity as well as advanced lymph node metastasis. HOPX promoter methylation is not only frequent and cancer-specific but also associated with aggressive phenotype in breast cancer. Epigenetic silencing of HOPX may have clinical potential as a biomarker in the treatment strategy of breast cancer patients.