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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number111909
JournalCell Reports
Volume42
Issue number1
DOIs
Publication statusPublished - Jan 31 2023

Keywords

  • ataxia-telangiectasia (ATM)
  • breast cancer
  • c-MYC
  • CP: Cancer
  • CP: Cell biology
  • DNA double-strand break repair
  • enhancer
  • estradiol
  • topoisomerase II

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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