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Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway

Oncogene volume 35, pages 4787–4797 (2016)Cite this article

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Abstract

The Wnt/β-catenin pathway has important roles in chemoresistance and multidrug resistance 1 (MDR1) expression in some cancers, but its involvement in breast cancer and the underlying molecular mechanism are undefined. In this study, we demonstrated that the Wnt/β-catenin pathway is activated in chemoresistant breast cancer cells. Using a Wnt pathway-specific PCR array screening assay, we detected that Pygo2, a newly identified Wnt/β-catenin pathway component, was the most upregulated gene in the resistant cells. Additional experiments indicated that Pygo2 activated MDR1 expression in the resistant cells via the Wnt/β-catenin pathway. Moreover, the inhibition of Pygo2 expression restored the chemotherapeutic drug sensitivity of the resistant cells and reduced the breast cancer stem cell population in these cells in response to chemotherapy. Importantly, these activities induced by Pygo2 were mediated by MDR1. We also determined the effect of Pygo2 on the sensitivity of breast tumors resistant to doxorubicin in a mouse model. Finally, RNA samples from 64 paired patient tumors (before and after chemotherapy) highly and significantly overexpressed Pygo2 and/or MDR1 after treatment, thus underlining a pivotal role for the Pygo2-mediated Wnt/β-catenin pathway in the clinical chemoresistance of breast cancer. Our data represent the first implication of the Wnt/β-catenin pathway in breast cancer chemoresistance and identify potential new targets to treat the recurrence of breast cancer.

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Acknowledgements

This work was supported by grants from the ‘973’ Project of the Ministry of Science and Technology (grant numbers 2013CB530600 to B-AL); the National Natural Science Foundation of China (grant numbers U1205023, 81472457, 81201616, 81201617 and 81272384 to B-AL, Q-CL and Q-FL); the Health-Education Joint Research Project of Fujian Province (grant numbers WKJ-FJ-23 to B-AL and Z-MZ); the Major Project of Science and Technology from the Department of Education (grant number 313051 to B-AL); the Natural Science Foundation of Fujian Province(grant numbers 2011D017 to Z-MZ); the Science and Technology Program of Xiamen (grant numbers 3502Z20114003 to H-QS) and ‘Project 111’ sponsored by the State Bureau of Foreign Experts and Ministry of Education (grant number B06016).

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Author notes

  1. Z-M Zhang, J-F Wu, Q-C Luo and Q-F Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Surgery, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China

    Z-M Zhang, Q-C Luo, Q-W Wu & H-Q She

  2. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Z-M Zhang, J-F Wu, Q-F Liu, G-D Ye & B-A Li

  3. Department of Bioengineering, College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, China

    J-F Wu

  4. Engineering Research Center of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Q-F Liu, G-D Ye & B-A Li

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  1. Z-M Zhang
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Correspondence to H-Q She or B-A Li.

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Zhang, ZM., Wu, JF., Luo, QC. et al. Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway. Oncogene 35, 4787–4797 (2016). https://doi.org/10.1038/onc.2016.10

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