Lestaurtinib Induces DNA Damage that is Related to Estrogen Receptor Activation

Authors

• J Mojumder
• S Vidhate
• YC Lu
• A Alshareef
• A Diano
• CL Johnson
• DL Pham
• JA Butman

Abstract

Numerous environmental chemicals pose potential risks to human health due to their ability to disrupt endocrine systems. As recent research indicated that estradiol induces DNA damage by activating estrogen receptors (ER), it is possible that environmental chemicals that act as hormones in the human body may also damage DNA. Additionally, BRCA1, whose mutations have been associated with breast cancer, is responsible for repairing estrogen-induced DNA damage. Therefore, ER-related DNA damage is of great concern to people with BRCA1 mutations. In this study, we developed a high-content imaging assay measuring γH2AX, a biomarker for DNA damage, and used this assay to test a subset of 907 compounds using breast cancer cells. From the screening, we identified 128 compounds that induced γH2AX. To examine which chemicals’ genotoxicity depended on ERα, we tested the effect of an ER inhibitor, tamoxifen, on genotoxicity. Tamoxifen treatment suppressed the induction of γH2AX by four compounds, indicating that these compounds induced γH2AX through ERα activation. These four compounds were further studied to assess their ERα activating capability and their induction of c-MYC, a target gene of ER signaling. Only lestaurtinib, a tyrosine kinase inhibitor, activated ERα, which was confirmed by both an ERα reporter gene assay and molecular docking analysis. Lestaurtinib also increased c-MYC expression. These data suggest lestaurtinib induces DNA damage through ERα activation. We established a high-throughput screening method with follow-up assays for DNA damage-related compound screening and identified a novel compound, lestaurtinib, that potentially promotes breast cancer by activating ER and inducing DNA damage.

Scientific Focus Area: Chemical Biology

This page was last updated on Monday, September 25, 2023