Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity

• Published in: Oncotarget 2016-12, Vol.7 (50), p.82158-82169
• Main Authors: Shi, Gongping, Yoshida, Yoko, Yuki, Kanako, Nishimura, Tomomi, Kawata, Yukiko, Kawashima, Masahiro, Iwaisako, Keiko, Yoshikawa, Kiyotsugu, Kurebayashi, Junichi, Toi, Masakazu, Noda, Makoto
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Benzamides - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; CpG Islands; DNA Methylation - drug effects; Dose-Response Relationship, Drug; Epigenesis, Genetic - drug effects; Exons; Female; GPI-Linked Proteins - genetics; Histone Deacetylase Inhibitors - pharmacology; Humans; MCF-7 Cells; Methotrexate - pharmacology; Middle Aged; Neoplasm Grading; Neoplasm Staging; Promoter Regions, Genetic; Pyridines - pharmacology; Research Paper; Time Factors
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8620

The membrane-anchored glycoprotein RECK negatively regulates multiple metalloproteinases and is frequently downregulated in tumors. Forced RECK expression in cancer cells results in suppression of tumor angiogenesis, invasion, and metastasis in xenograft models. A previous methylome study on breast cancer tissues detected inverse correlation between RECK CpG methylation (in an intron-1 region) and relapse-free survival. In this study, we focused on another region of the RECK CpG island (a promoter/exon-1 region) and found an inverse correlation between its methylation and RECK-inducibility by an HDAC inhibitor, MS275, among a panel of breast cancer cell lines (n=15). In clinical samples (n=62), RECK intron-1 methylation was prevalent among luminal breast cancers as reported previously (26 of 38 cases; 68%) and particularly enriched in tumors of the ER+PR- subclass (10 of 10 cases) and of higher histological grades (Grade 2 and 3; 28 of 43 cases; P=0.006). In about a half of these cases, promoter/exon-1 methylation was absent, and hence, RECK may be inducible by certain drugs such as MS275. Our results indicate the value of combined use of two RECK methylation markers for predicting prognosis and drug-sensitivity of breast cancers.