Chronic Alcohol Exposure Induces Persistent DNA Damage Response Signaling and Sensitizes Breast Epithelial Cells to PARP Inhibition.

Authors

Ming Zhao, Zhikun Ma, Amanda B Parris, Jadyn Beacham, Xiaohe Yang

Published in

bioRxiv : the preprint server for biology. Sep 22, 2026. Epub Sep 22, 2026.

Abstract

Chronic alcohol consumption is associated with increased breast cancer risk; however, the long-term effects of alcohol exposure on DNA damage response (DDR) signaling and therapeutic vulnerability in breast epithelial cells remain incompletely understood. In the present study, we established a chronic alcohol exposure model using immortalized human breast epithelial MCF-10A cells to investigate persistent alterations in DNA damage signaling and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. MCF-10A cells that chronically exposed to 0.2% alcohol for 20 weeks and then withdrew alcohol treatment for 4 weeks still retained elevated γH2AX levels and sustained activation of ATM/ATR-associated DDR pathways. Chronic alcohol-exposed cells also exhibited increased sensitivity to the PARP inhibitors olaparib and veliparib, as demonstrated by reduced cell viability, decreased clonogenic survival, and enhanced apoptosis. Mechanistically, olaparib induced greater G2/M checkpoint activation and replication-associated DNA damage in chronic alcohol-exposed cells compared with control cells. In addition, chronic alcohol exposure increased PARP expression and enhanced activation of DDR signaling following PARP inhibition. These findings demonstrate that chronic alcohol exposure induces persistent DNA repair stress and sensitizes breast epithelial cells to PARP inhibition. Our study suggests that chronic alcohol-associated genomic stress may create potential vulnerability to PARP inhibition.
Chronic alcohol exposure induces persistent DNA damage response signaling in MCF-10A cells.Chronic alcohol-exposed cells exhibit enhanced sensitivity to the PARP inhibitors.Chronic alcohol exposure increased G2/M arrest induced by PARP inhibitor and replication-associated DNA damage.Chronic alcohol exposure upregulates PARP expression and alters DDR signaling responses.

PMID:
42818220
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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