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

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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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          Author and article information

          Journal
          Oncogene
          Oncogene
          Springer Nature
          1476-5594
          0950-9232
          Sep 08 2016
          : 35
          : 36
          Affiliations
          [1 ] Department of Breast Surgery, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China.
          [2 ] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
          [3 ] Department of Bioengineering, College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, China.
          [4 ] Engineering Research Center of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
          Article
          onc201610
          10.1038/onc.2016.10
          26876203

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