Cyclin E2 Overexpression Is Associated with Endocrine Resistance but not Insensitivity to CDK2 Inhibition in Human Breast Cancer Cells
Cyclin E2 Overexpression Is Associated with Endocrine Resistance but not Insensitivity to CDK2 Inhibition in Human Breast Cancer Cells
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DOI：
10.1158/1535-7163.mct-11-0963
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发表时间：
2012-07-01
影响因子：
5.7
通讯作者：
Musgrove, Elizabeth A.
中科院分区：
文献类型：
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作者：
Caldon, C. Elizabeth;Sergio, C. Marcelo;Musgrove, Elizabeth A.
细胞周期蛋白E2，而不是细胞周期蛋白E1，包括在几个基因的签名，预测疾病进展，无论是他莫昔芬耐药或转移性乳腺癌。因此，我们研究了细胞周期蛋白E2在体外抗雌激素抵抗中的作用及其通过细胞周期蛋白依赖性激酶（CDK）抑制进行治疗靶向的潜力。CCNE 2的高表达，而非CCNE 1，是管腔型B和HER 2亚型乳腺癌的特征，并且强烈预测内分泌治疗后较短的无远处转移生存期。MCF-7乳腺癌细胞经抗雌激素处理后，cyclin E2 mRNA和蛋白表达下调，cyclin E2-CDK 2活性降低。然而，这种调节失去了他莫昔芬耐药（MCF-7 TAMR）细胞，细胞周期蛋白E2过表达。T-47 D乳腺癌细胞中细胞周期蛋白E1或E2的表达赋予急性抗雌激素抵抗，表明细胞周期蛋白E过表达有助于他莫昔芬耐药细胞的抗雌激素抵抗。细胞周期蛋白E1或E2的异位表达也降低了对CDK 4抑制的敏感性，但对CDK 2抑制无影响。三苯氧胺耐药细胞的增殖受到RNAi介导的细胞周期蛋白E1、细胞周期蛋白E2或CDK 2敲低的抑制。此外，CDK 2抑制E-cyclin过表达细胞和他莫昔芬耐药细胞恢复对他莫昔芬或CDK 4抑制的敏感性。因此，细胞周期蛋白E2过表达是对内分泌治疗和CDK 4抑制的抵抗的潜在机制。CDK 2抑制剂有望成为内分泌抵抗性疾病联合治疗的一个组成部分，因为它们有效抑制细胞周期蛋白E1和E2过表达细胞，并增强其他治疗药物的疗效。Mol Cancer Ther; 11（7）; 1488-99. (c)2012年AACR。
Cyclin E2, but not cyclin E1, is included in several gene signatures that predict disease progression in either tamoxifen-resistant or metastatic breast cancer. We therefore examined the role of cyclin E2 in antiestrogen resistance in vitro and its potential for therapeutic targeting through cyclin-dependent kinase (CDK) inhibition. High expression of CCNE2, but not CCNE1, was characteristic of the luminal B and HER2 subtypes of breast cancer and was strongly predictive of shorter distant metastasis-free survival following endocrine therapy. After antiestrogen treatment of MCF-7 breast cancer cells, cyclin E2 mRNA and protein were downregulated and cyclin E2-CDK2 activity decreased. However, this regulation was lost in tamoxifen-resistant (MCF-7 TAMR) cells, which overexpressed cyclin E2. Expression of either cyclin E1 or E2 in T-47D breast cancer cells conferred acute antiestrogen resistance, suggesting that cyclin E overexpression contributes to the antiestrogen resistance of tamoxifen-resistant cells. Ectopic expression of cyclin E1 or E2 also reduced sensitivity to CDK4, but not CDK2, inhibition. Proliferation of tamoxifen-resistant cells was inhibited by RNAl-mediated knockdown of cyclin E1, cyclin E2, or CDK2. Furthermore, CDK2 inhibition of E-cyclin overexpressing cells and tamoxifen-resistant cells restored sensitivity to tamoxifen or CDK4 inhibition. Cyclin E2 overexpression is therefore a potential mechanism of resistance to both endocrine therapy and CDK4 inhibition. CDK2 inhibitors hold promise as a component of combination therapies in endocrine-resistant disease as they effectively inhibit cyclin E1 and E2 overexpressing cells and enhance the efficacy of other therapeutics. Mol Cancer Ther; 11(7); 1488-99. (c) 2012 AACR.