Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer

Zhao, Ping; Sun, Jian; Huang, Xinwei; Zhang, Xiangwu; Liu, Xin; Liu, Rong; Du, Guangshi; Gan, Wenqiang; Yang, Chuanyu; Tang, Yiyin; Chen, Ceshi; Jiang, Dewei

doi:10.7150/ijbs.82567

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Theranostics

International Journal of Medical Sciences

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Journal of Cancer

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Int J Biol Sci 2023; 19(6):1861-1874. doi:10.7150/ijbs.82567 This issue Cite

Research Paper

Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer

Ping Zhao^1#, Jian Sun^1#, Xinwei Huang^2#, Xiangwu Zhang¹, Xin Liu¹, Rong Liu³, Guangshi Du⁴, Wenqiang Gan^5,6, Chuanyu Yang⁵, Yiyin Tang^1✉, Ceshi Chen^1,5,7✉, Dewei Jiang^5,6✉

1. The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118 China
2. Key Laboratory of The Second Affiliated Hospital of Kuming Medical College, Kunming, 650101, China
3. Translational Cancer Research Center, Peking University First Hospital, Beijing, 100034 China
4. Translational Medicine Research Center, Guizhou Medical University, Guiyang, 550025 China
5. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201 China
6. Kunming College of Life Sciences, University of the Chinese Academy of Sciences, Kunming, 650204 China
7. Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500 China
# Equal contribution

Citation:

Zhao P, Sun J, Huang X, Zhang X, Liu X, Liu R, Du G, Gan W, Yang C, Tang Y, Chen C, Jiang D. Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer. Int J Biol Sci 2023; 19(6):1861-1874. doi:10.7150/ijbs.82567. https://www.ijbs.com/v19p1861.htm

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Abstract

Ephrin type-A receptor 2 (EphA2) is a member of the tyrosine receptor kinases, a family of membrane proteins recognized as potential anticancer targets. EphA2 highly expressed in a variety of human cancers, playing roles in proliferation, migration, and invasion. However, whether and how EphA2 regulates basal-like breast cancer (BLBC) cell stemness and chemoresistance has not been revealed. Here, KLF5 was proven to be a direct transcription factor for EphA2 in BLBC cells, and its expression was positively correlated in clinical samples from breast cancer patients. The inflammatory factor TNF-α could promote BLBC cell stemness partially by activating the KLF5-EphA2 axis. Moreover, phosphorylation of EphA2 at S897 (EphA2 pS897) induced by TNF-α and PTX/DDP contributes to chemoresistance of BLBC. Furthermore, the EphA2 inhibitor ALW-II-41-27 could effectively reduce EphA2 pS897 and tumor cell stemness in vitro and significantly enhance the sensitivity of xenografts to the chemotherapeutic drugs PTX and DDP in vivo. Clinically, tumor samples from breast patients with less response to neoadjuvant chemotherapy showed a high level of EphA2 pS897 expression. In conclusion, KLF5-EphA2 promotes stemness and drug resistance in BLBC and could be a potential target for the treatment of BLBC.

Keywords: EphA2, TNF-α, KLF5, BLBC stem cells, Chemoresistance, ALW-II-41-27

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APA

Zhao, P., Sun, J., Huang, X., Zhang, X., Liu, X., Liu, R., Du, G., Gan, W., Yang, C., Tang, Y., Chen, C., Jiang, D. (2023). Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer. International Journal of Biological Sciences, 19(6), 1861-1874. https://doi.org/10.7150/ijbs.82567.

ACS

Zhao, P.; Sun, J.; Huang, X.; Zhang, X.; Liu, X.; Liu, R.; Du, G.; Gan, W.; Yang, C.; Tang, Y.; Chen, C.; Jiang, D. Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer. Int. J. Biol. Sci. 2023, 19 (6), 1861-1874. DOI: 10.7150/ijbs.82567.

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CSE

Zhao P, Sun J, Huang X, Zhang X, Liu X, Liu R, Du G, Gan W, Yang C, Tang Y, Chen C, Jiang D. 2023. Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer. Int J Biol Sci. 19(6):1861-1874.

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