| Abstract: |
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. ©2010 AACR. |
| Keywords: |
signal transduction; controlled study; protein expression; human cell; promoter region; nonhuman; antineoplastic agents; mouse; animals; mice; in situ hybridization, fluorescence; breast cancer; smad protein; transforming growth factor beta; epidermal growth factor receptor 2; cell line; animal experiment; animal model; protein binding; rna interference; cell line, tumor; breast neoplasms; phosphorylation; cancer inhibition; oncogene; blotting, western; gene expression regulation, neoplastic; antibodies, monoclonal; regulatory mechanism; mice, nude; reverse transcriptase polymerase chain reaction; promoter regions, genetic; myc protein; proto-oncogene proteins c-akt; breast epithelium; epithelium cell; protein biosynthesis; receptor, erbb-2; senescence; trastuzumab; proto-oncogene proteins c-myc; breast carcinogenesis; cell aging; protein isoforms; ccaat enhancer binding protein beta; ccaat-enhancer-binding protein-beta
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