Her2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2

Oncogene. 2020 Nov;39(47):7034-7050. doi: 10.1038/s41388-020-01481-y. Epub 2020 Sep 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Datasets as Topic
  • Disease-Free Survival
  • Epithelial Cells
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System / genetics*
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Neoplasm Metastasis / pathology
  • Primary Cell Culture
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins / metabolism*
  • Receptor, ErbB-2 / metabolism*
  • S-Phase Kinase-Associated Proteins / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Proto-Oncogene Proteins
  • S-Phase Kinase-Associated Proteins
  • SKP2 protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human
  • Proteasome Endopeptidase Complex