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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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS HER2 PROMOTES EARLY DISSEMINATION OF BREAST CANCER BY SUPPRESSING THE P38-MK2-HSP27 PATHWAY THAT IS TARGETABLE BY WIP1

INHIBITION Article 26 August 2020 THE EXTRACELLULAR-REGULATED PROTEIN KINASE 5 (ERK5) ENHANCES METASTATIC BURDEN IN TRIPLE-NEGATIVE BREAST CANCER THROUGH FOCAL ADHESION PROTEIN KINASE

(FAK)-MEDIATED REGULATION OF CELL ADHESION Article Open access 12 May 2021 PAK5 PROMOTES THE TRASTUZUMAB RESISTANCE BY INCREASING HER2 NUCLEAR ACCUMULATION IN HER2-POSITIVE BREAST CANCER

Article Open access 21 April 2025 CHANGE HISTORY * _ 11 FEBRUARY 2021 A Correction to this paper has been published: https://doi.org/10.1038/s41388-021-01652-5 _ REFERENCES * Fidler IJ. The

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glioblastoma. Cancer Cell. 2016;29:563–73. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * These authors

contributed equally: Guanwen Wang, Juan Wang AUTHORS AND AFFILIATIONS * 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 * Department of Immunology, School of Medicine,

Nankai University, Tianjin, China Guanwen Wang, Juan Wang, Antao Chang, Shan Huang, Shuang Yang & Rong Xiang Authors * Guanwen Wang View author publications You can also search for this

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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. CORRESPONDING AUTHORS Correspondence to Rong Xiang or Peiqing Sun. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors

declare that they have no conflict of interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and

institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTAL INFORMATION RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 26 February 2020 * Revised: 21 August 2020 * Accepted: 17 September 2020 * Published: 28 September 2020 * Issue Date:

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