Transforming growth factor β engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab
Transforming growth factor β engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab
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DOI：
10.1128/mcb.00787-08
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发表时间：
2008-09-01
影响因子：
5.3
通讯作者：
Arteaga, Carlos L.
中科院分区：
文献类型：
--
作者：
Wang, Shizhen Emily;Xian, Bin;Arteaga, Carlos L.
在HER2过表达的乳腺上皮细胞中，转化生长因子β（TGF-β）激活磷脂酰肌醇-3激酶（PI3K）/Akt，并增强存活和迁移。用TGF-β处理或表达活化的TGF-β I型受体（具有突变T204D的Alk5 [Alk5（T204D）]）诱导TACE/ADAM 17的磷酸化及其易位到细胞表面，导致TGF-α、双调蛋白和调蛋白的分泌增加。反过来，这些配体增强了p85与ErbB3的结合并激活了PI3K/Akt。TACE或ErbB3的RNA干扰阻止了TGF-β诱导的Akt活化和细胞侵袭。在HER2过表达细胞中用TGF-β或Alk5（T204D）表达处理降低了它们对HER2抗体曲妥珠单抗的敏感性。抑制Alk5、PI3K、TACE或ErbB3可恢复对曲妥珠单抗的敏感性。Alk5（T204D）表达诱导的基因签名与浸润性乳腺癌患者的不良临床结局相关。这些结果表明，通过作用于ErbB配体脱落，过量的TGF-β可能导致（i）用生长因子调节肿瘤微环境，这些生长因子可以与相邻的基质细胞和内皮细胞结合;（ii）增强下游ErbB受体的信号传导，从而导致肿瘤进展和对抗HER2治疗的耐药性;以及（iii）乳腺癌女性的临床结局较差。
In HER2-overexpressing mammary epithelial cells, transforming growth factor beta (TGF-beta) activated phosphatidylinositol-3 kinase (PI3K)/Akt and enhanced survival and migration. Treatment with TGF-beta or expression of an activated TGF-beta type I receptor (Alk5 with the mutation T204D [Alk5(T204D)]) induced phosphorylation of TACE/ADAM17 and its translocation to the cell surface, resulting in increased secretion of TGF-alpha, amphiregulin, and heregulin. In turn, these ligands enhanced the association of p85 with ErbB3 and activated PI3K/Akt. RNA interference of TACE or ErbB3 prevented TGF-beta-induced activation of Akt and cell invasiveness. Treatment with TGF-beta or expression of Alk5(T204D) in HER2-overexpressing cells reduced their sensitivity to the HER2 antibody trastuzumab. Inhibition of Alk5, PI3K, TACE, or ErbB3 restored sensitivity to trastuzumab. A gene signature induced by Alk5(T204D) expression correlated with poor clinical outcomes in patients with invasive breast cancer. These results suggest that by acting on ErbB ligand shedding, an excess of TGF-beta may result in (i) conditioning of the tumor microenvironment with growth factors that can engage adjacent stromal and endothelial cells; (ii) potentiation of signaling downstream ErbB receptors, thus contributing to tumor progression and resistance to anti-HER2 therapies; and (iii) poor clinical outcomes in women with breast cancer.