@article{16d1fb19250c43089aa38f0a301348da,
title = "ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen",
abstract = "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.",
keywords = "ataxia-telangiectasia (ATM), breast cancer, c-MYC, CP: Cancer, CP: Cell biology, DNA double-strand break repair, enhancer, estradiol, topoisomerase II",
author = "Najnin, {Rifat Ara} and {Al Mahmud}, {Md Rasel} and Rahman, {Md Maminur} and Shunichi Takeda and Hiroyuki Sasanuma and Hisashi Tanaka and Yasuhiro Murakawa and Naoto Shimizu and Salma Akter and Masatoshi Takagi and Takuro Sunada and Shusuke Akamatsu and Gang He and Junji Itou and Masakazu Toi and Mary Miyaji and Tsutsui, {Kimiko M.} and Scott Keeney and Shintaro Yamada",
note = "Funding Information: The authors thank Kyoto University Center for Anatomical, Pathological and Forensic Medical Researches, as well as Memorial Sloan Kettering Cancer Center (MSKCC) Molecular Cytology core for histology sample preparation; Y. Agata (Shiga University of Medical Science) for help in analysis of 3C experiments; F. Cort{\'e}s-Ledesma (Spanish National Cancer Research Center) for TDP2 and dTDP2 cDNAs; T.T. Paull (University of Texas at Austin), Y. Shiloh (Tel Aviv University), P.A. Jeggo (University of Sussex), and C.A. Austin (Newcastle University) for critical reading; Jessica Tamanini (ETediting, UK) for English editing; and S. Kim, D. Ontoso, D.Y. Eng, S. Pu, A.H. Polash, L.K. Saha, R. Akagawa, and other members of the S.T. and the S.K. laboratories for discussions. Kyoto University Medical Research Support Center was supported by AMED Grant JP19am0101092. MSKCC core facilities were supported by National Institutes of Health (NIH) Cancer Center Core Grant P30 CA008748. Work was supported by JSPS KAKENHI (16H12595 and 16H06306) and the JSPS Core-to-Core Program, A. Advanced Research Networks (to S.T.); JSPS KAKENHI (19H04267) (to H.S.); the National Cancer Institute (2 R01 CA149385) and the Department of Defense (W81XWH-18-1-0058) (to H.T.); JSPS KAKENHI (18H03992 and 20KK0186) (to Y.M.); NIH Grant R35 GM118092 (to S.K.); JSPS KAKENHI (19K20449 and 21K07148), Fujiwara Memorial Foundation, the Takeda Science Foundation, and the MEXT Program for the Development of Next-generation Leading Scientists with Global Insight (L-INSIGHT) (to S.Y.). Conceptualization, R.A.N. S.T. H.S. and S.Y.; methodology, R.A.N. H.S. H.T. Y.M. and I.J.; investigation, R.A.N. M.R.A.M. M.M.R. H.S. N.S. S.Akter, T.S. G.H. J.I. and S.Y.; resources, H.T. Y.M. M.Takagi, S.Akamatsu, M.Toi, M.M. K.M.T. and S.K.; writing – original draft, R.A.N. S.T. and S.Y.; writing – review and editing preparation, R.A.N. S.T. S.K. and S.Y.; supervision, S.T. H.S. S.Akamatsu, I.J. M.Toi, S.K. and S.Y.; funding, S.T. H.S. H.T. Y.M. S.K. and S.Y. The authors have no conflicts of interest directly relevant to the content of this article. We support inclusive, diverse, and equitable conduct of research. Funding Information: The authors thank Kyoto University Center for Anatomical, Pathological and Forensic Medical Researches, as well as Memorial Sloan Kettering Cancer Center (MSKCC) Molecular Cytology core for histology sample preparation; Y. Agata (Shiga University of Medical Science) for help in analysis of 3C experiments; F. Cort{\'e}s-Ledesma (Spanish National Cancer Research Center) for TDP2 and dTDP2 cDNAs; T.T. Paull (University of Texas at Austin), Y. Shiloh (Tel Aviv University), P.A. Jeggo (University of Sussex), and C.A. Austin (Newcastle University) for critical reading; Jessica Tamanini (ETediting, UK) for English editing; and S. Kim, D. Ontoso, D.Y. Eng, S. Pu, A.H. Polash, L.K. Saha, R. Akagawa, and other members of the S.T. and the S.K. laboratories for discussions. Kyoto University Medical Research Support Center was supported by AMED Grant JP19am0101092 . MSKCC core facilities were supported by National Institutes of Health ( NIH ) Cancer Center Core Grant P30 CA008748 . Work was supported by JSPS KAKENHI ( 16H12595 and 16H06306 ) and the JSPS Core-to-Core Program, A. Advanced Research Networks (to S.T.); JSPS KAKENHI ( 19H04267 ) (to H.S.); the National Cancer Institute ( 2 R01 CA149385 ) and the Department of Defense ( W81XWH-18-1-0058 ) (to H.T.); JSPS KAKENHI ( 18H03992 and 20KK0186 ) (to Y.M.); NIH Grant R35 GM118092 (to S.K.); JSPS KAKENHI ( 19K20449 and 21K07148 ), Fujiwara Memorial Foundation , the Takeda Science Foundation, and the MEXT Program for the Development of Next-generation Leading Scientists with Global Insight (L-INSIGHT) (to S.Y.). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2023",
month = jan,
day = "31",
doi = "10.1016/j.celrep.2022.111909",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}
