Her2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2
| Autor: | Guanwen Wang, Juan Wang, Antao Chang, Dongmei Cheng, Shan Huang, Dan Wu, Sherona Sirkisoon, Shuang Yang, Hui-Kuan Lin, Hui-Wen Lo, Rong Xiang, Peiqing Sun |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Proteasome Endopeptidase Complex MAP Kinase Signaling System Receptor ErbB-2 Primary Cell Culture Datasets as Topic Breast Neoplasms Mice Transgenic p38 p38 Mitogen-Activated Protein Kinases Disease-Free Survival Article early dissemination Mice Mammary Glands Animal Her2 Tpl2 breast cancer Cell Movement Cell Line Tumor Proto-Oncogene Proteins Genetics Animals Humans Breast Neoplasm Metastasis skin and connective tissue diseases Molecular Biology S-Phase Kinase-Associated Proteins Mammary Neoplasms Experimental Epithelial Cells MAP Kinase Kinase Kinases Gene Expression Regulation Neoplastic Proteolysis Female Skp2 |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions before primary tumors appear are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how Her2 downregulates p38 is unclear. Here, we demonstrate that in early lesion breast cancer models, Her2 inhibits p38 by inducing Skp2 through Akt-mediated phosphorylation, which promotes ubiquitination and proteasomal degradation of Tpl2, a p38 MAP3K. The early disseminating cells are Her2+Skp2highTpl2lowp-p38lowE-cadherinlow in the MMTV-Her2 breast cancer model. In human breast carcinoma, high Skp2 and low Tpl2 expression are associated with the Her2+ status; Tpl2 expression positively correlates with that of activated p38; Skp2 expression negatively correlates with that of Tpl2 and activated p38. Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo. These findings identify the Her2-Akt-Skp2-Tpl2-p38 cascade as a novel mechanism mediating breast cancer early dissemination and a potential target for novel therapies targeting early metastatic dissemination. |
| Databáze: | OpenAIRE |
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