Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

了解乳腺癌亚型之间的根本差异推动了治疗的进步；然而，基底样乳腺癌（BLBC）在临床上仍然难以治疗。由于 BLBC 表现出 DNA 修复酶和细胞周期检查点的改变，因此阐明该亚型中存在的基因组不稳定因素有可能揭示新的抗癌策略。在这里，我们证明 BLBC 对铁硫簇 (ISC) 生物合成的抑制特别敏感，并将 DNA 聚合酶 epsilon (POLE) 鉴定为一种包含 ISC 的蛋白质，是该表型的基础。在 BLBC 细胞中，POLE 抑制会导致复制叉停滞、DNA 损伤以及类衰老状态或细胞死亡。相比之下，管腔乳腺癌和未转化的乳腺细胞在 POLE 抑制后保持活力，但变得依赖于 ATR/CHK1/CDC25A/CDK2 DNA 损伤反应轴。我们发现 CDK1/2 靶点在 BLBC 肿瘤中选择性地表现出过度磷酸化，表明 CDK2 过度活跃是一种基因组完整性漏洞，可通过靶向 POLE 来利用。