Oncology Programme, Institute for Research in Biomedicine, Barcelona, Spain.
Cancer Res. 2010 Dec 1;70(23):9927-36. doi: 10.1158/0008-5472.CAN-10-0869. Epub 2010 Nov 23.
Tumor progression requires ablation of suppressor functions mediated by transforming growth factor β (TGFβ) 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 TGFβ- and OIS-mediated tumor suppression by switching expression of 2 functionally distinct isoforms of the transcription factor C/EBPβ, 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 TGFβ, 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.
肿瘤的发展需要消除转化生长因子 β（TGFβ）信号和癌基因诱导的衰老（OIS）介导的抑制功能，但在特定类型的乳腺癌中，这些功能如何被消除仍然未知。在这项研究中，我们表明，HER2 过表达的乳腺癌细胞通过切换转录因子 C/EBPβ 的两种功能不同的异构体的表达来避免 TGFβ 和 OIS 介导的肿瘤抑制，先前已经表明 C/EBPβ 参与了乳腺癌的发展。HER2 信号激活翻译调节因子 CUGBP1，有利于转录抑制性异构体 LIP 的产生，而不是活性异构体 LAP。LIP 的过表达阻止了 LAP/Smad 转录阻遏复合物在 TGFβ 作用下在 MYC 启动子上的组装，并干扰了 OIS 反应的激活。用 HER2 抗体曲妥珠单抗处理 HER2 转化的乳腺上皮细胞会降低 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，通过该机制，HER2 协同沉默肿瘤抑制，这有助于该癌基因在乳腺癌中的效力。
