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

ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM pre-vents 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 estro-gens. 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. Af-ter 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 overex-pression 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.

Automated summary

ATM gene mutation carriers have a higher risk of developing estrogen-receptor-positive breast cancer (BC). ATM is involved in the early transcriptional response to estrogens through its interaction with topoisomerase II (TOP2) and helps in the repair of TOP2-DNA double-strand breaks (DSBs). Defective repair of TOP2-dependent DSBs after estrogen exposure leads to changes in enhancer activation and overexpression of genes, including the c-MYC oncogene.