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首页> 外文期刊>Cell cycle >Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity
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Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity

机译：细胞周期调节剂cyclin D1和CDK4 / 6在乳腺癌的迁移和干细胞样活性中具有雌激素受体依赖性发散功能

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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 2 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.
机译：细胞周期蛋白D1及其结合伴侣CDK4 / 6是细胞周期进程的重要调节剂，与癌症进程有关。我们的目的是研究这些蛋白质在其他重要肿瘤生物学特征中的潜在调控作用。使用一组乳腺癌细胞系和人类原发性乳腺癌样品，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CDK4 / 6的表达，对迁移和依赖雌激素受体（ER）的干样细胞活性均具有相反的作用。抑制细胞周期蛋白D1或CDK4 / 6分别增加或减少ER-ve（ER阴性）和ER + ve（ER阳性）乳腺癌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细胞迁移和干细胞样细胞活性降低，而ER + ve乳腺癌细胞的活性增加。目前正在临床试验中，用细胞周期蛋白D1和CDK4 / 6（Flavopiridol / PD0332991）抑制剂治疗乳腺癌细胞可模仿siRNA治疗所产生的效果。在2个ER-ve细胞系中重新表达ER足以克服siRNA或细胞周期蛋白D1和CDK4 / 6的临床抑制剂的作用。总之，细胞周期蛋白D1和CDK4 / 6在调节迁移和干细胞样活性方面具有替代作用。此外，这些作用高度依赖于ER的表达。这些结果的重要性增加了我们对癌症生物学的普遍了解，但最重要的是，可以在诊断上用于预测对乳腺癌细胞周期抑制的治疗反应。

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