19. Dongyi Zhao, PhD

Accumulating DNA damage, specifically interstrand crosslinks (ICLs), may drive the development of basal-like breast cancer in BRCA1-deficient mammary epithelial cells (MECs). This study investigates the role of DNA damage in promoting a stem cell-like state, contributing to tumor initiation in high-risk individuals. Using BRCA1-deficient mouse models and organoid cultures, we show that ICLs, induced by cisplatin, enhance proliferation and alter gene expression patterns, pushing MECs toward basal-like and mesenchymal characteristics. Key regulators in this process, such as SOX10 and FGF signaling, are activated following DNA damage, which promotes cellular plasticity and a stem-like state. SOX10 and FGF1 were particularly implicated in upregulating mesenchymal markers, reinforcing cell fate changes in the damaged MECs.

To explore potential therapeutic targets, we tested the inhibition of Wnt signaling, a pathway associated with DNA damage responses in cancer. Treatment with a Clostridioides difficile toxin fragment (TcdBFBD) significantly inhibited proliferation in organoid models, reversing the proliferative effects of cisplatin-induced damage. This suggests that suppressing Wnt signaling could mitigate tumor initiation in BRCA1-deficient cells.

These findings reveal critical pathways through which DNA damage fosters basal-like features in mammary cells, marking a potential pathway for targeted prevention and treatment strategies in BRCA1-associated breast cancer. The study highlights the interplay between DNA repair deficiencies and oncogenic signaling as drivers of cancer cell fate transitions, offering new insights into molecular targets for early intervention.