Oncotarget

Research Papers:

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

Gongping Shi, Yoko Yoshida _, Kanako Yuki, Tomomi Nishimura, Yukiko Kawata, Masahiro Kawashima, Keiko Iwaisako, Kiyotsugu Yoshikawa, Junichi Kurebayashi, Masakazu Toi and Makoto Noda

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Oncotarget. 2016; 7:82158-82169. https://doi.org/10.18632/oncotarget.8620

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Abstract

Gongping Shi1, Yoko Yoshida2, Kanako Yuki2, Tomomi Nishimura3, Yukiko Kawata3, Masahiro Kawashima3, Keiko Iwaisako4, Kiyotsugu Yoshikawa2, Junichi Kurebayashi5, Masakazu Toi2,3, Makoto Noda1,2

1Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

2Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

3Department of Breast Surgery, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

4Department of Target Therapy and Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

5Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, 701-0192, Japan

Correspondence to:

Yoko Yoshida, e-mail: yyoshida@virus.kyoto-u.ac.jp

Makoto Noda, e-mail: mnoda@virus.kyoto-u.ac.jp

Keywords: RECK, DNA methylation, CpG island, breast cancer, entinostat

Received: January 29, 2016    Accepted: March 28, 2016    Published: April 06, 2016

ABSTRACT

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.


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