Open AccessHer2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2
Author(s) -
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
Publication year - 2020
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-020-01481-y
Subject(s) - cancer research , protein kinase b , biology , breast cancer , skp2 , metastatic breast cancer , cancer , metastasis , p38 mitogen activated protein kinases , signal transduction , phosphorylation , ubiquitin , protein kinase a , ubiquitin ligase , microbiology and biotechnology , biochemistry , gene , genetics
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 + Skp2 high Tpl2 low p-p38 low E-cadherin low 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.