Disruption of Cyclin-Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer–specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers. Mol Cancer Ther; 17(1); 306–15. ©2017 AACR.

中文翻译：

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评估 CDK12 蛋白表达作为乳腺癌 DNA 损伤反应靶向治疗的潜在新型生物标志物

已知细胞周期蛋白依赖性激酶 12 (CDK12) 的破坏会导致 DNA 修复缺陷和对铂盐和 PARP1/2 抑制剂的敏感性。然而，CDK12 也被提议作为乳腺癌的致癌基因。因此，我们旨在通过 IHC 在独立的乳腺癌队列中评估 CDK12 蛋白表达的频率和分布，并将其与结果和基因组状态相关联。通过 IHC，我们发现 21% 的未选择原发性乳腺癌 CDK12 高，10.5% 不存在。CDK12 阳性与 HER2 阳性相关，但考虑到 HER2 状态，它不是乳腺癌特异性生存的独立预测因子；然而，缺乏 CDK12 蛋白表达与三阴性表型显着相关。有趣的是，CDK12 蛋白缺失与包括 ATR、Ku70/Ku80、PARP1、DNA-PK 和 γH2AX 在内的许多 DDR 蛋白的表达降低有关，表明 CDK12 相关 DDR 失调在乳腺癌中的新机制。我们的数据表明，CDK12 在乳腺癌中的诊断性 IHC 定量是可行的，CDK12 缺失可能意味着 DDR 功能有缺陷。这可能具有重要的治疗意义，特别是对于三阴性乳腺癌。摩尔癌症治疗；17(1)；306-15。©2017 AACR。这可能具有重要的治疗意义，特别是对于三阴性乳腺癌。摩尔癌症治疗；17(1)；306-15。©2017 AACR。这可能具有重要的治疗意义，特别是对于三阴性乳腺癌。摩尔癌症治疗；17(1)；306-15。©2017 AACR。