Department of Breast Surgery, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Oncogene. 2016 Sep 8;35(36):4787-97. doi: 10.1038/onc.2016.10. Epub 2016 Feb 15.
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.
Wnt/β-catenin 通路在某些癌症的化疗耐药性和多药耐药 1（MDR1）表达中具有重要作用，但它在乳腺癌中的作用及其潜在的分子机制尚不清楚。在这项研究中，我们证明了 Wnt/β-catenin 通路在耐药乳腺癌细胞中被激活。通过 Wnt 通路特异性 PCR 阵列筛选检测，我们发现新鉴定的 Wnt/β-catenin 通路成分 Pygo2 在耐药细胞中是上调最明显的基因。进一步的实验表明，Pygo2 通过 Wnt/β-catenin 通路激活耐药细胞中的 MDR1 表达。此外，抑制 Pygo2 的表达恢复了耐药细胞对化疗药物的敏感性，并减少了这些细胞中对化疗的乳腺癌干细胞群体。重要的是，Pygo2 诱导的这些活性是由 MDR1 介导的。我们还在小鼠模型中确定了 Pygo2 对多柔比星耐药的乳腺肿瘤敏感性的影响。最后，来自 64 对患者肿瘤（化疗前后）的 RNA 样本在治疗后高度且显著过表达 Pygo2 和/或 MDR1，从而强调了 Pygo2 介导的 Wnt/β-catenin 通路在乳腺癌临床化疗耐药性中的关键作用。我们的数据代表了 Wnt/β-catenin 通路在乳腺癌化疗耐药性中的首次暗示，并确定了治疗乳腺癌复发的潜在新靶点。
