| First Author | Najnin RA | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 1 | Pages | 111909 |
| PubMed ID | 36640339 | Mgi Jnum | J:333451 |
| Mgi Id | MGI:7434090 | Doi | 10.1016/j.celrep.2022.111909 |
| Citation | Najnin RA, et al. (2023) ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen. Cell Rep 42(1):111909 |
| abstractText | 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. |
