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

Chronic consumption of alcohol has been linked to higher breast cancer risk; however, the long-term consequences of alcohol exposure on DNA damage response (DDR) signaling and susceptibility to PARP inhibitors in breast epithelial cells are not yet fully understood. To address this gap, researchers created a model using human breast MCF-10A epithelial cells that were chronically exposed to 0.2% alcohol for 20 weeks before being taken off alcohol for 4 weeks.

Surprisingly, even after the alcohol was withdrawn, these cells continued to exhibit higher levels of {gamma}H2AX and maintained activation of ATM/ATR-associated DDR pathways. Moreover, chronic alcohol-exposed cells showed a heightened sensitivity to PARP inhibitors like olaparib and veliparib. This increased sensitivity was characterized by lower cell viability, reduced clonogenic survival, and amplified apoptosis rates.

The study further revealed that chronic alcohol exposure induced greater G2/M checkpoint activation and replication-associated DNA damage in these cells compared to control cells. Additionally, it led to increased PARP expression and enhanced activation of DDR signaling upon PARP inhibition. These findings suggest that chronic alcohol exposure generates persistent DDR stress and makes breast epithelial cells more vulnerable to PARP inhibition.

The researchers propose that alterations in genomic stability caused by alcohol may render these cells more susceptible to PARP inhibitor therapy.