Details

Autor(en) / Beteiligte

• Najnin, Rifat Ara
• Al Mahmud, Md Rasel
• Rahman, Md Maminur
• Takeda, Shunichi
• Sasanuma, Hiroyuki
• Tanaka, Hisashi
• Murakawa, Yasuhiro
• Shimizu, Naoto
• Akter, Salma
• Takagi, Masatoshi
• Sunada, Takuro
• Akamatsu, Shusuke
• He, Gang
• Itou, Junji
• Toi, Masakazu
• Miyaji, Mary
• Tsutsui, Kimiko M.
• Keeney, Scott
• Yamada, Shintaro

Titel

ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen

Ist Teil von

• Cell reports (Cambridge), 2023-01, Vol.42 (1), p.111909-111909, Article 111909

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •ATM promotes the repair of DNA TOP2-dependent DNA breaks•Unrepaired TOP2-dependent DSBs impair early transcriptional responses to estrogens•TOP2 generates a DNA break at the c-MYC enhancer after estrogen exposure•Loss of ATM results in c-MYC gene overexpression after estrogen exposure Women carrying an ATM gene mutation have an increased risk for estrogen-receptor-positive breast cancer. Najnin et al. highlight the role of ATM in suppressing oncogene overexpression and abnormal cellular proliferation in the mammary epithelium upon estrogen stimuli.