Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer.
Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer.
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DOI：
10.1530/erc-11-0112
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发表时间：
2011-08
影响因子：
3.9
通讯作者：
Yee D
中科院分区：
文献类型：
--
作者：
Lange CA;Yee D
大多数（约70%）乳腺癌在诊断时为类固醇激素受体（SR）阳性。针对雌激素受体α (ERα)作用的内分泌治疗（他莫昔芬、托瑞米芬、氟维司汀）或雌激素合成（芳香酶抑制剂：来曲唑、阿那曲唑、依西美坦或卵巢抑制）是临床的主要治疗方法。然而，高达50%的SR+乳腺癌对这些临床干预措施表现出新生或获得性耐药性。对内分泌治疗的抵抗机制通常包括信号转导途径的上调和/或激活，这些信号转导途径输入细胞周期调节。细胞周期蛋白D1是细胞周期蛋白依赖性蛋白激酶4和6 （CDK4/6）的调控亚基，是多种信号通路的汇聚点。在最近一篇题为“治疗性激活视网膜母细胞瘤（RB）：重建内分泌治疗耐药乳腺癌的细胞周期控制”的论文中，Thangavel等人报道了在内分泌耐药的多种乳腺癌细胞系模型中，面对ER消融，cyclin D1表达和RB磷酸化得以维持。rb功能障碍定义了与腔内b型乳腺癌相关的独特基因标记，并预测了对内分泌治疗的不良反应。值得注意的是，一种新的CDK4/6抑制剂（PD-0332991）能够通过与细胞衰老最一致的机制诱导生长停滞。在这篇综述中，这些发现在SRs作为细胞周期进程的重要介质，以及乳腺癌进展典型的细胞周期检查点控制的频繁丢失的背景下进行了讨论。这些研究为使用CDK4/6抑制剂形式的细胞抑制剂有效稳定内分泌抵抗性乳腺癌提供了新的希望。
The majority (~70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor α (ERα) action (tamoxifen, toremifene, fulvestrant) or estrogen synthesis (aromatase inhibitors: letrozole, anastrozole, exemestane; or ovarian suppression) are a clinical mainstay. However, up to 50% of SR+breast cancers exhibit de novo or acquired resistance to these clinical interventions. Mechanisms of resistance to endocrine therapies often include upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways. In a recent paper entitled ‘Therapeutically Activating Retinoblastoma (RB): Reestablishing Cell Cycle Control in Endocrine Therapy-Resistant Breast Cancer’, Thangavel et al. reported maintenance of cyclin D1 expression and RB phosphorylation in the face of ER ablation in multiple breast cancer cell line models of endocrine resistance. RB-dysfunction defined a unique gene signature that was associated with luminal B-type breast cancer and predictive of poor response to endocrine therapies. Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence. In this review, these findings are discussed in the context of SRs as important mediators of cell cycle progression, and the frequent loss of cell cycle checkpoint control that typifies breast cancer progression. These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors.