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

Rifat Ara Najnin1, Md Rasel Al Mahmud1, Md Maminur Rahman1

  • 1Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Kyoto 606-8501, Japan.

Cell Reports
|January 14, 2023
PubMed

Insights

ATM loss in breast cancer (BC) cells allows estrogen to drive c-MYC oncogene overexpression by disrupting DNA repair. This ATM-driven suppression of estrogen

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • ATM gene mutations predispose individuals to estrogen-receptor-positive breast cancer (BC).
  • ATM's role in tissue-specific oncogenesis following its loss is not fully understood.
  • ATM is known to activate p53, a tumor suppressor, in all cells.

Purpose of the Study:

  • To investigate the role of ATM in the early transcriptional response to estrogens.
  • To elucidate the mechanisms by which ATM loss contributes to breast cancer development.

Main Methods:

  • Analysis of estrogen's transcriptional response in human BC cells with and without ATM.
  • Investigated the role of topoisomerase II (TOP2) in generating and repairing DNA double-strand breaks (DSBs).
  • Utilized CRISPR/Cas9 gene editing to induce DSBs at the c-MYC enhancer.
  • Examined estrogen-induced c-Myc protein levels in ATM-deficient mouse mammary epithelial cells.

Main Results:

  • ATM controls the early transcriptional response to estrogens, dependent on TOP2 activity.
  • Estrogen exposure induces TOP2-dependent DSBs at the c-MYC enhancer in human BC cells.
  • Defective repair of these DSBs leads to altered enhancer activation and c-MYC oncogene overexpression.
  • CRISPR/Cas9-induced DSBs at the enhancer also resulted in c-MYC overexpression.
  • Estrogen treatment increased c-Myc protein in ATM-deficient mouse mammary cells.

Conclusions:

  • ATM suppresses estrogen-driven proliferation by inhibiting c-MYC overexpression.
  • Defective DNA repair of TOP2-generated DSBs at the c-MYC enhancer contributes to BC oncogenesis after ATM loss.
  • This mechanism may explain tissue-specific oncogenesis in ATM mutation carriers.
Keywords:
CP: CancerCP: Cell biologyDNA double-strand break repairataxia-telangiectasia (ATM)breast cancerc-MYCenhancerestradioltopoisomerase II

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