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Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair

Ali Pedram1, Mahnaz Razandi, Albert J Evinger

  • 1Department of Medicine, University of California, Irvine, Irvine CA 92717, USA.

Molecular Biology of the Cell
|May 30, 2009
PubMed

Insights

Estrogen restrains DNA damage response by blocking ATR kinase activation in ER-positive breast cancer cells. This estrogen action may be relevant to breast cancer development and treatment.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • DNA damage activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase signaling cascade.
  • The mechanisms restraining ATR activity, particularly in the context of breast cancer, are not fully understood.

Purpose of the Study:

  • To investigate how estrogen receptor (ER) signaling influences ATR activation in response to DNA damage in ER-positive breast cancer cells.
  • To elucidate the molecular pathways by which estrogen restrains ATR activity and its downstream effects on DNA repair and genomic stability.

Main Methods:

  • Treatment of ER-positive breast cancer cells with DNA-damaging agents (UV, ionizing radiation, hydroxyurea) and 17-beta-estradiol (E(2)).
  • Assessment of ATR kinase activity, phosphorylation of p53 and Chk1, and protein-protein interactions (ATR-TopBP1, Claspin-Chk1).
  • Analysis of cell cycle progression, DNA repair foci (gammaH2AX, Rad51), and chromosomal damage.

Main Results:

  • 17-beta-estradiol (E(2)) substantially blocks ATR activation via plasma membrane-localized ERalpha, reducing ATR-dependent phosphorylation of p53 and Chk1.
  • E(2)/ER reduces ATR-TopBP1 association and inhibits Claspin-Chk1 association through PI3K/AKT signaling, preventing G2/M checkpoint activation.
  • E(2) delays DNA repair, prolongs the resolution of DNA damage markers, and increases chromosomal damage, indicating impaired DNA repair.

Conclusions:

  • Estrogen receptor signaling restrains ATR cascade activation in ER-positive breast cancer cells.
  • This estrogen-mediated restraint of ATR activity impacts DNA repair dynamics and genomic stability.
  • The inhibition of ATR signaling by estrogen may represent a novel mechanism relevant to breast cancer progression and therapeutic strategies.

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