Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer.
Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer.
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DOI：
10.18632/oncotarget.14689
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
Keyomarsi K
中科院分区：
文献类型：
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作者：
Alexander A;Karakas C;Chen X;Carey JP;Yi M;Bondy M;Thompson P;Cheung KL;Ellis IO;Gong Y;Krishnamurthy S;Alvarez RH;Ueno NT;Hunt KK;Keyomarsi K
炎性乳腺癌（IBC）是一种恶性乳腺癌，迫切需要新的治疗策略。临床诊断为IBC （n = 147）和非IBC乳腺癌（n = 2510）的女性肿瘤的免疫组化分析显示，在非IBC病例中，细胞质周期蛋白E与预后不良高度相关（P < 0.001），而在IBC病例中，核细胞周期蛋白E和细胞质周期蛋白E均提示预后不良。这些结果强调了周期蛋白E/CDK2复合物作为一种新的治疗靶点的效用。由于IBC细胞系对CDK2抑制剂dinaciclib和meriolin 5高度敏感，我们开发了一种高通量生存试验（HTSA）来设计基于cyclin E和CDK2存在的新的顺序组合策略。通过对14个细胞系的研究，我们发现dinaciclib增强了dna损伤化疗的活性，在dinaciclib之后进行化疗，而紫杉醇则不是这样。我们还发现了DNA修复相关基因的特征，这些基因被dinaciclib下调，这表明整体DNA修复受到抑制，延长的DNA损伤导致细胞凋亡。综上所述，我们的研究结果表明，cdk2靶向联合治疗IBC可能是可行的策略，值得未来的临床研究。
Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.