Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells
Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells
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DOI：
10.1038/sj.onc.1206012
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发表时间：
2002-11-21
期刊：
影响因子：
8
通讯作者：
Michalides, R
中科院分区：
文献类型：
--
作者：
Bindels, EMJ;Lallemand, F;Michalides, R
雌激素受体介导的转录可通过G1/S周期蛋白D1、E或A的过表达而增强，无论在雌二醇存在或不存在的情况下。过量的G1/S周期蛋白也阻止了纯抗雌激素ICI 182780对雌激素受体（ER）转激活的抑制。Cyclin D1介导这种不依赖于其CDK4/6伙伴复合物形成的交易激活。这就提出了一种可能性，即G1/S细胞周期蛋白的过度表达使er阳性乳腺癌的生长不依赖于激素，并且对抗雌激素治疗产生耐药性。G1/S细胞周期蛋白瞬时转染er阳性乳腺癌细胞株T47D和MCF7可克服ICI 182780诱导的生长停滞。各种周期蛋白D1突变体克服ICI 182780介导的生长停滞的能力，与它们在ICI 182780存在下刺激基于周期蛋白A和E2F启动子的报告活性的能力相一致。转染突变的细胞周期蛋白D1 (cyclin D1- ke)，不能结合CDK4，并且在ICI 182780存在的情况下会反激活内质网，不能刺激ICI 182780处理的细胞的增殖。另一方面，不能刺激ERE转激活的cyclin D1-LALA可以克服ICI 182780细胞周期阻滞。此外，使用cyclin D1和CDK4催化失活突变体（CDK4- dn）瞬时转染T47D细胞表明，观察到的效果是由于与CDK抑制剂结合。然而，在稳定转染的MCF7细胞中，cyclin D1的六倍过表达并没有克服ICI 182780介导的生长停滞。这些结果表明，细胞周期蛋白D1对雌激素受体的CDK非依赖性转激活本身并不足以导致乳腺癌细胞的雌二醇非依赖性生长，而G1/S细胞周期蛋白的大量过表达则能够做到这一点，这很可能是通过捕获CDK抑制剂实现的。
Estrogen receptor-mediated transcription is enhanced by overexpression of G1/S cyclins D1, E or A in the presence as well in the absence of estradiol. Excess of G1/S cyclins also prevents the inhibition of transactivation of estrogen receptor (ER) by the pure antiestrogen ICI 182780. Cyclin D1 mediates this transactivation independent of complex formation to its CDK4/6 partner. This raises the possibility that overexpression of G1/S cyclins renders growth of ER-positive breast cancer hormone-independent and resistant to treatment with antiestrogens. Transient transfection of ER-positive breast cancer cell lines T47D and MCF7 with G1/S cyclins could overcome the growth arrest induced by ICI 182780 treatment. The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A- and E2F- promoter based reporter activities in the presence of ICI 182780. Transfection of a mutant cyclin D1 (cyclin D1-KE) that was unable to bind CDK4 and was reported to transactivate ER in the presence of ICI 182780, could not stimulate proliferation in ICI 182780 treated cells. On the other hand, cyclin D1-LALA, which is unable to stimulate ERE transactivation, could overcome the ICI 182780 cell cycle arrest. Furthermore, transient transfection of T47D cells using cyclin D1 together with a catalytic inactive mutant of CDK4 (CDK4-DN) indicated that the observed effect is due to binding to CDK inhibitors. However, a moderate, sixfold overexpression of cyclin D1 in stably transfected MCF7 cells did not overcome the ICI 182780 mediated growth arrest. These results indicate that CDK-independent transactivation of the estrogen receptor by cyclin D1 is by itself, not sufficient to result in estradiol-independent growth of breast cancer cells, whereas a vast overexpression of G1/S cyclins is able to do so, most likely by capturing of CDK inhibitors.