Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.

基底样乳腺癌（BLBC）是一种侵袭性乳腺癌，对靶向治疗和化疗反应不佳。为了定义 BLBC 的治疗靶向子集，我们检查了两个标记：细胞周期蛋白 E1 和BRCA1丢失。在高级别浆液性卵巢癌 (HGSOC) 中，这些标志物是相互排斥的，并定义了治疗子集。我们对 BLBC 测试了相同的假设。使用富含BRCA1丢失的 BLBC 队列，我们​​发现BRCA1丢失和细胞周期蛋白 E1 蛋白高表达之间存在趋同性，而 HGSOC 中CCNE1扩增驱动细胞周期蛋白 E1 增加。在细胞系中， BRCA1丢失与细胞周期期间稳定的细胞周期蛋白 E1 相关， BRCA1 siRNA 导致细胞周期蛋白 E1 增加，同时磷酸化细胞周期蛋白 E1 T62 减少。细胞周期蛋白 E1 T62 突变为丙氨酸增加了细胞周期蛋白 E1 的稳定性。我们发现，BLBC 队列中细胞周期蛋白 E1/ BRCA1高突变的肿瘤的磷酸化 T62 也减少，支持了这一假设。由于细胞周期蛋白 E1/CDK2 可以保护细胞免受 DNA 损伤，并且细胞周期蛋白 E1 在BRCA1突变癌症中升高，因此我们假设 CDK2 抑制会使这些癌症对 PARP 抑制敏感。 CDK2 抑制诱导 DNA 损伤，并与 PARP 抑制剂协同作用，降低同源重组缺陷细胞系（包括BRCA1突变细胞系）的细胞活力。采用 PARP 和 CDK2 抑制联合治疗BRCA1突变 BLBC 患者来源的异种移植模型，导致肿瘤消退并提高生存率。 我们得出的结论是， BRCA1状态和高细胞周期蛋白 E1 有潜力作为预测生物标志物来决定 CDK 抑制剂/PARP 抑制剂组合在 BLBC 中的治疗用途。