ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen
Rifat Ara Najnin,
Md Rasel Al Mahmud,
Md Maminur Rahman,
Shunichi Takeda,
Hiroyuki Sasanuma,
Hisashi Tanaka,
Yasuhiro Murakawa,
Naoto Shimizu,
Salma Akter,
Masatoshi Takagi,
Takuro Sunada,
Shusuke Akamatsu,
Gang He,
Junji Itou,
Masakazu Toi,
Mary Miyaji,
Kimiko M. Tsutsui,
Scott Keeney,
Shintaro Yamada
Affiliations
Rifat Ara Najnin
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan
Md Rasel Al Mahmud
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan
Md Maminur Rahman
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan
Shunichi Takeda
Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
Hiroyuki Sasanuma
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan
Hisashi Tanaka
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Yasuhiro Murakawa
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy; Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Institute for Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
Naoto Shimizu
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan
Salma Akter
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan
Masatoshi Takagi
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
Takuro Sunada
Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shougoin Kawahara-cho, Kyoto 606-8507, Japan
Shusuke Akamatsu
Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shougoin Kawahara-cho, Kyoto 606-8507, Japan
Gang He
Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
Junji Itou
Breast Cancer Unit, Kyoto University Hospital, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Masakazu Toi
Breast Cancer Unit, Kyoto University Hospital, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Mary Miyaji
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Kimiko M. Tsutsui
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Scott Keeney
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Shintaro Yamada
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan; Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Corresponding author
Summary: ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis.
