HER2 Silences Tumor Suppression in Breast Cancer Cells by Switching Expression of C/EBPβ Isoforms
HER2 Silences Tumor Suppression in Breast Cancer Cells by Switching Expression of C/EBPβ Isoforms
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DOI：
10.1158/0008-5472.can-10-0869
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Gomis, Roger R.
中科院分区：
文献类型：
--
作者：
Arnal-Estape, Anna;Tarragona, Maria;Gomis, Roger R.
肿瘤进展需要消融由转化生长因子β (TGF β)信号和癌基因诱导的衰老（OIS）介导的抑制功能，但这些功能如何在特定亚型乳腺癌中被取消尚不清楚。在这项研究中，我们发现her2过表达的乳腺癌细胞通过转换转录因子C/EBP β的2种功能不同的异构体的表达来避免TGF β和ois介导的肿瘤抑制，而转录因子C/EBP β先前与乳腺癌的发展有关。HER2信号通路激活翻译调节因子CUGBP1，这有利于产生转录抑制异构体LIP而不是活性异构体LAP。LIP过表达可阻止LAP/Smad转录抑制复合物在MYC启动子上组装以响应TGF β，并干扰OIS应答的激活。用HER2抗体曲妥珠单抗治疗HER2转化的乳腺上皮细胞可降低LIP水平，恢复这些抑制反应。我们的发现揭示了一种新的机制，通过这种机制，HER2以协调一致的方式沉默肿瘤抑制，促进了这种癌基因在乳腺癌中的效力。癌症Res;70 (23);9927 - 36。AACR (C) 2010。
Tumor progression requires ablation of suppressor functions mediated by transforming growth factor beta (TGF beta) signaling and by oncogene-induced senescence (OIS), but how these functions are canceled in specific subtypes of breast cancer remains unknown. In this study, we show that HER2-overexpressing breast cancer cells avert TGF beta- and OIS-mediated tumor suppression by switching expression of 2 functionally distinct isoforms of the transcription factor C/EBP beta, which has been implicated previously in breast cancer development. HER2 signaling activates the translational regulatory factor CUGBP1, which favors the production of the transcriptionally inhibitory isoform LIP over that of the active isoform LAP. LIP overexpression prevents the assembly of LAP/Smad transcriptional repressor complexes on the MYC promoter in response to TGF beta, and interferes with activation of OIS responses. Treatment of HER2-transformed mammary epithelial cells with the HER2 antibody trastuzumab reduces LIP levels, restoring these suppressor responses. Our findings reveal a novel mechanism through which HER2 silences tumor suppression in a concerted manner, contributing to the potency of this oncogene in breast cancer. Cancer Res; 70( 23); 9927-36. (C)2010 AACR.