Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity
Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity
复制标题
DOI：
10.4161/cc.25403
复制
发表时间：
2013-08-01
期刊：
影响因子：
4.3
通讯作者：
Landberg, Goran
中科院分区：
文献类型：
--
作者：
Lamb, Rebecca;Lehn, Sophie;Landberg, Goran
细胞周期蛋白D1及其结合伴侣CDK 4/6是细胞周期进程的重要调节因子，并与癌症进展有关。我们的目的是研究这些蛋白在其他基本肿瘤生物学特征中的潜在调节作用。使用一组乳腺癌细胞系和原发性人类乳腺癌样本，我们已经证明了这些细胞周期调节剂在迁移和干细胞样细胞活性中的重要性。siRNA用于靶向细胞周期蛋白D1和CDK 4/6表达，对依赖于雌激素受体（ER）表达的迁移和干细胞样细胞活性具有相反的作用。细胞周期蛋白D1或CDK 4/6的抑制分别增加或减少ER-ve（ER阴性）和ER+ve（ER阳性）乳腺癌中的迁移和干细胞样细胞活性。此外，过表达的细胞周期蛋白D1导致ER-ve细胞中的迁移和干细胞样细胞活性降低，而ER+ve乳腺癌细胞中的活性增加。目前在临床试验中，用细胞周期蛋白D1和CDK 4/6的抑制剂（Flavopiridol/PD 0332991）治疗乳腺癌细胞，模拟了用siRNA治疗观察到的效果。在两个ER-ve细胞系中重新表达ER足以克服siRNA或cyclin D1和CDK 4/6的临床抑制剂的影响。结论：cyclin D1和CDK 4/6在调节迁移和干细胞活性方面具有交替作用。此外，这些作用高度依赖于ER的表达。这些结果的意义增加了我们对癌症生物学的一般理解，但最重要的是，可以用于诊断预测乳腺癌细胞周期抑制的治疗反应。
Cyclin D1 and its binding partners CDK4/6 are essential regulators of cell cycle progression and are implicated in cancer progression. Our aim was to investigate a potential regulatory role of these proteins in other essential tumor biological characteristics. Using a panel of breast cancer cell lines and primary human breast cancer samples, we have demonstrated the importance of these cell cycle regulators in both migration and stem-like cell activity. siRNA was used to target cyclin D1 and CDK4/6 expression, having opposing effects on both migration and stem-like cell activity dependent upon estrogen receptor (ER) expression. Inhibition of cyclin D1 or CDK4/6 increases or decreases migration and stem-like cell activity in ER-ve (ER-negative) and ER+ve (ER-positive) breast cancer, respectively. Furthermore, overexpressed cyclin D1 caused decreased migration and stem-like cell activity in ER-ve cells while increasing activity in ER+ve breast cancer cells. Treatment of breast cancer cells with inhibitors of cyclin D1 and CDK4/6 (Flavopiridol/PD0332991), currently in clinical trials, mimicked the effects observed with siRNA treatment. Re-expression of ER in two ER-ve cell lines was sufficient to overcome the effects of either siRNA or clinical inhibitors of cyclin D1 and CDK4/6.In conclusion, cyclin D1 and CDK4/6 have alternate roles in regulation of migration and stem-like cell activity. Furthermore, these effects are highly dependent upon expression of ER. The significance of these results adds to our general understanding of cancer biology but, most importantly, could be used diagnostically to predict treatment response to cell cycle inhibition in breast cancer.