ATM suppresses c-MYC overexpression in the mammary epithelium in response to estrogen Journal Article
| Authors: | Najnin, R. A.; Al Mahmud, R.; Rahman, M.; Takeda, S.; Sasanuma, H.; Tanaka, H.; Murakawa, Y.; Shimizu, N.; Akter, S.; Takagi, M.; Sunada, T.; Akamatsu, S.; He, G.; Itou, J.; Toi, M.; Miyaji, M.; Tsutsui, K. M.; Keeney, S.; Yamada, S. |
| Article 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. © 2022 The Author(s) |
| Keywords: | breast cancer; dna double-strand break repair; c-myc; estradiol; enhancer; topoisomerase ii; cp: cancer; ataxia-telangiectasia (atm); cp: cell biology |
| Journal Title: | Cell Reports |
| Volume: | 42 |
| Issue: | 1 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2023-01-31 |
| Start Page: | 111909 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2022.111909 |
| PROVIDER: | scopus |
| PUBMED: | 36640339 |
| PMCID: | PMC10023214 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Shintaro Yamada -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work