Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
Department of Clinical Gene Therapy and Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Sci Rep. 2018 Mar 5;8(1):4013. doi: 10.1038/s41598-018-22340-7.
Recent studies suggest a functional involvement of Epithelial-Mesenchymal Transition (EMT) in tumor chemoresistance. Specifically, EMT is associated with chemoresistance and poor prognosis in triple-negative breast cancer. However, no effective therapy targeting EMT has been developed. Here, we report that periostin, an extracellular matrix protein, was induced upon chemotherapy and tightly correlated with the EMT gene signature and poor prognosis in breast cancer. In triple-negative breast cancer xenografts, chemotherapy upregulated periostin expression in tumor cells, triggered expansion of mesenchymal tumor cells and promoted invasion in residual tumors. Knockdown of periostin inhibited outgrowth and invasion of mesenchymal tumor cells upon chemotherapy. Furthermore, chemotherapy upregulated cancer-specific variants of periostin and application of a blocking antibody specifically targeting those variants overcame chemoresistance and halted disease progression without toxicity. Together, these data indicate that periostin plays a key role in EMT-dependent chemoresistance and is a promising target to overcome chemoresistance in triple-negative breast cancer.
最近的研究表明上皮-间质转化（EMT）在肿瘤化疗耐药中具有功能作用。具体而言，EMT 与三阴性乳腺癌的化疗耐药和预后不良相关。然而，尚未开发出针对 EMT 的有效治疗方法。在这里，我们报告细胞外基质蛋白骨桥蛋白在化疗后被诱导，与 EMT 基因特征和乳腺癌的不良预后密切相关。在三阴性乳腺癌异种移植模型中，化疗上调了肿瘤细胞中骨桥蛋白的表达，触发了间充质肿瘤细胞的扩增，并促进了残留肿瘤的侵袭。骨桥蛋白敲低抑制了化疗后间充质肿瘤细胞的生长和侵袭。此外，化疗上调了骨桥蛋白的癌症特异性变体，应用特异性针对这些变体的阻断抗体克服了化疗耐药性并阻止了疾病进展而没有毒性。总之，这些数据表明骨桥蛋白在 EMT 依赖性化疗耐药中起关键作用，是克服三阴性乳腺癌化疗耐药的有前途的靶点。
