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Her2 promotes early dissemination of breast cancer by suppressing the p38-MK2-Hsp27 pathway that is targetable by Wip1 inhibition

Oncogene volume 39, pages 6313–6326 (2020)Cite this article

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Abstract

Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2highp-p38lowp-MK2lowp-Hsp27low, which also exist in human breast carcinoma tissues. Suppression of p38 and MK2 by Her2 reduces MK2-mediated Hsp27 phosphorylation, and unphosphorylated Hsp27 binds to β-catenin and enhances its phosphorylation by Src, leading to β-catenin activation and disseminating phenotypes in early lesion breast cancer cells. Pharmacological inhibition of MK2 promotes, while inhibition of a p38 phosphatase Wip1 suppresses, early dissemination in vivo. These findings identify Her2-mediated suppression of the p38-MK2-Hsp27 pathway as a novel mechanism for cancer early dissemination, and provide a basis for new therapies targeting early metastatic dissemination in Her2+ breast cancer.

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Fig. 1: Her2 suppresses phosphorylation of MK2 and Hsp27 in mammary epithelial cells and early lesions of MMTV-Her2 mouse mammary glands.
Fig. 2: Her2 promotes the disseminating phenotypes by suppressing p38 in Her2+ early lesion mammary epithelial cells.
Fig. 3: Her2 promotes the disseminating phenotypes by suppressing p38-mediated MK2 activation in Her2+ early lesion breast cancer cells.
Fig. 4: Her2 promotes the disseminating phenotypes by suppressing MK2-mediated phosphorylation of Hsp27 in Her2+ early lesion breast cancer cells.
Fig. 5: Suppression of the p38-MK2-Hsp27 pathway by Her2 activates β-catenin through Src-mediated phosphorylation.
Fig. 6: Pharmacological inhibition of MK2 promotes early dissemination in the MMTV-Her2 model.
Fig. 7: Pharmacological inhibition of Wip1 inhibits early dissemination in the MMTV-Her2 model.

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Acknowledgements

This study was supported by NIH/NCI grants CA131231, CA172115 (PS) and Bilateral Inter-Governmental S&T Cooperation Project grants from Ministry of Science and Technology of China (81972882 and 2018YFE0114300, RX), and by Cell Engineering and Tumor Tissue and Pathology Shared Resources of WFBCCC, supported by NCI’s Cancer Center Support Grant (P30CA012197). PS is supported by the Anderson Oncology Research Professorship.

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

Authors and Affiliations

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

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

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

    Juan Wang, Guanwen Wang, Dongmei Cheng, Shan Huang, Antao Chang, Xiaoming Tan, Dan Wu, Andy T. Liu & Peiqing Sun

  3. Department of Respiratory Disease, South Campus, Renji Hospital, School of Medicine Shanghai Jiaotong University, Shanghai, China

    Xiaoming Tan

  4. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Andy T. Liu

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Contributions

JW, GW, SY, RX, and PS conceived and designed the study. JW, GW, DC, SH, AC, XT, DW, QW, and SZ executed the experiments; JW, GW, AC, and PS analyzed and interpreted the data. JW, GW, SY, RX, and PS wrote and/or reviewed the paper.

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Wang, J., Wang, G., Cheng, D. et al. Her2 promotes early dissemination of breast cancer by suppressing the p38-MK2-Hsp27 pathway that is targetable by Wip1 inhibition. Oncogene 39, 6313–6326 (2020). https://doi.org/10.1038/s41388-020-01437-2

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