Estrogen Inhibits ATR Signaling to Cell Cycle Checkpoints and DNA Repair

Abstract

DNA damage activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase signal cascade. How this system is restrained is not understood. We find that in estrogen receptor (ER)-positive breast cancer cells, UV or ionizing radiation and hydroxyurea rapidly activate ATR-dependent phosphorylation of endogenous p53 and Chk1. 17-beta-estradiol (E(2)) substantially blocks ATR activity via plasma membrane-localized ERalpha. E(2)/ER reduces the enhanced association of ATR andTopBP1 proteins that follows DNA damage and strongly correlates to ATR activity. E(2) inhibits ATR activation through rapid PI3K/AKT signaling: AKT phosphorylates TopBP1 at Serine 1159, thereby preventing the enhanced association of ATR with TopBP1 after DNA damage. E(2) also inhibits Claspin:Chk1 protein association via AKT phosphorylation of Chk1, preventing Chk1 signaling to the G2/M checkpoint. ATR-phosphorylation of p53 induces p21 transcription, prevented by E(2)/ER. E(2) delays the assembly and prolongs the resolution of gammaH2AX and Rad51 nuclear foci and delays DNA repair. E(2)/ER also increases the chromosomal damage seen from cell exposure to IR. Therefore, the restraint of ATR cascade activation may be a novel estrogen action relevant to breast cancer.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Inhibition of normal DNA repair signaling may simulate genetically based loss of DNA damage response signaling molecules such as ataxia telangiectasia mutated (ATM), ataxia telangiectasia and rad3-related protein (ATR), DNAdependent protein kinase (DNAPK), breast cancer 1 (BRCA1) and BRCA 2, p53, and Chk2 that predispose normal cells to acquire transforming mutations [79]. A recent report showed that in ER-positive breast cancer cells, DNA damaging agents including Uv, ionizing radiation, and hydroxyurea rapidly activated ATR-dependent phosphorylation of endogenous p53 and Chk1 [80]. The pathway involves extranuclear actions by E2 via plasma membrane-localized ERα and the activation of PI3K/Akt signaling pathway.…”

“…Ligand-bound ERα regulates ATR activity by potentiating the Akt-mediated phosphorylation of DNA topoisomerase 2-binding protein 1 (TOPBP1) at serine 1159, which prevents the binding of TOPBP1 with ATR after DNA damage. Since the association of Chk1 with claspin is important for Chk1 activity, E2-ERα regulates Chk1 activity via Akt-mediated phosphorylation of Chk1, which prevents its association with claspin and the signal transduction to the G2/M checkpoint [80]. ATM protein expression is found to be aberrantly reduced more frequently among BRCA1-and BRCA2 mutation carrier tumors than in non-BRCA1/2 mutation carrier tumors, therefore reduced ATM expression was found more often in ER-and PR-negative breast cancer indicating loss-of-function interaction among these molecules [81].…”

Reversibility of pre-malignant estrogen-induced epigenetic changes

“…Furthermore, estrogen metabolism produces genotoxic by-products that can directly damage DNA, 9 thereby disrupting normal cellular processes such as apoptosis, proliferation and DNA repair. 1,[10][11][12] As a strong promoting agent, estrogen-driven proliferation not only increases the number of estrogen-responsive cells but also potentially stimulates clonal expansion of pre-cancerous cells. [13][14][15] Interestingly, the promotion of these initiated cells requires continuous exposure to estrogen to progress preneoplastic lesions to a state of transformation.…”

Akt Switches TopBP1 Function from Checkpoint Activation to Transcriptional Regulation through Phosphoserine Binding-Mediated Oligomerization

“…Estrogen has been shown to inhibit ATR activation through phosphatidylinositol 3-kinase (PI3K)/Akt action, which inhibits the interaction between ATR and wild-type TopBP1 but not S1159A mutant TopBP1 (21). Estrogen also inhibits the interaction between Chk1 and claspin via phosphorylation of Chk1 by Akt (21).…”

“…Estrogen also inhibits the interaction between Chk1 and claspin via phosphorylation of Chk1 by Akt (21). Therefore, the underlying mechanism by which Akt inhibits the checkpoint response may involve multiple regulators.…”