Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins
Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins
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DOI：
10.1038/sj.onc.1207331
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发表时间：
2004-04-29
期刊：
影响因子：
8
通讯作者：
Hynes, NE
中科院分区：
文献类型：
--
作者：
Koziczak, M;Holbro, T;Hynes, NE
成纤维细胞生长因子受体（FGFR）酪氨酸激酶的过表达已被发现在许多人乳腺癌，并已与不良的患者预后。为了了解FGFR介导乳腺癌细胞增殖的机制，我们使用了一种低分子量化合物PD 173074，它选择性地抑制FGFR酪氨酸激酶活性和自磷酸化。这种潜在的抗癌剂导致MDA-MB-415、MDA-MB-453和SUM 52乳腺癌细胞的G1生长停滞。我们的分析表明，FGFR信号通过D型细胞周期蛋白与细胞周期机制联系在一起。PD 173074介导的FGFR活性抑制导致细胞周期蛋白D1和细胞周期蛋白D2表达下调，细胞周期蛋白D/cdk 4活性抑制，并因此导致pRB磷酸化减少。逆转录病毒介导的细胞周期蛋白D1的异位表达阻止了PD 173074处理的细胞中的pRB磷酸化不足和细胞周期G1阻滞，这表明D细胞周期蛋白在FGFR驱动的乳腺癌细胞增殖中起着重要作用。在MDA-MB-415和MDA-MB 453细胞中，FGFR活性的抑制引起MAPK的下调。在SUM 52细胞中，MAPK和PI 3 K信号通路均被抑制。总之，这里显示的结果描述了FGFR促进乳腺癌细胞增殖的机制。
Overexpression of fibroblast growth factor receptor ( FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.