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

Oncogene volume 39, pages 7034–7050 (2020)Cite this article

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A Correction to this article was published on 10 February 2021

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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.

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Fig. 1: Reduced Tpl2 levels correlate with Her2+ status and reduced p38 activation in cell and mouse models of early lesion breast cancer and early-lesion human breast cancer tissues, and with increased Skp2 expression in early-lesion human breast cancer tissues.
Fig. 2: Her2 mediates migration, invasion, and EMT by downregulating Tpl2 expression in mammary epithelial cells isolated from 14 to 18-week-old MMTV-Her2 mice with early lesions.
Fig. 3: Her2 reduces Tpl2 protein expression through Skp2-mediated ubiquitination and proteasomal degradation.
Fig. 4: Skp2 mediates Her2-induced Tpl2 and p38 suppression and migration, invasion and EMT in early lesion breast cancer cells.
Fig. 5: Skp2 promotes migration, invasion and EMT by suppressing Tpl2 in Her2+ early lesion breast cancer cells.
Fig. 6: Her2 induces Skp2 expression and function through Akt-mediated phosphorylation.
Fig. 7: Pharmacological inhibition of Tpl2 suppresses the p38 pathway and promotes the disseminating phenotypes in Her2+ early lesion breast cancer cells and enhances early dissemination in vivo in the MMTV-Her2 mouse model.

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Acknowledgements

We thank Cell Engineering and Tumor Tissue and Pathology Shared Resources of WFBCCC for support. This study was supported by NIH/NCI grants CA131231, CA172115, and P30CA012197 (PS) and Bilateral Inter-Governmental S&T Cooperation Project grants from Ministry of Science and Technology of China (81972882 and 2018YFE0114300) (RX). PS is an Anderson Oncology Research Professor.

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  1. These authors contributed equally: Guanwen Wang, Juan Wang

Authors and Affiliations

  1. Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA

    Guanwen Wang, Juan Wang, Antao Chang, Dongmei Cheng, Shan Huang, Dan Wu, Sherona Sirkisoon, Hui-Kuan Lin, Hui-Wen Lo & Peiqing Sun

  2. Department of Immunology, School of Medicine, Nankai University, Tianjin, China

    Guanwen Wang, Juan Wang, Antao Chang, Shan Huang, Shuang Yang & Rong Xiang

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  1. Guanwen Wang
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Contributions

GW, JW, RX, and PS conceived and designed the study. GW, JW, MD, SH, AC, and DW executed the experiments; GW, JW, AC, KL, SS, HL, HL, and PS analyzed and interpreted the data. GW, JW, HL, HL, RX, and PS wrote and/or reviewed the manuscript.

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Correspondence to Rong Xiang or Peiqing Sun.

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Wang, G., Wang, J., Chang, A. et al. Her2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2. Oncogene 39, 7034–7050 (2020). https://doi.org/10.1038/s41388-020-01481-y

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