From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
the Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, and.
J Biol Chem. 2014 Jun 6;289(23):16057-71. doi: 10.1074/jbc.M113.529552. Epub 2014 Apr 15.
Previous studies have demonstrated that Artemin (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein, we report that ARTN mediates acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. Ligands that increase HER2 activity increased ARTN expression in HER2-positive mammary carcinoma cells, whereas trastuzumab inhibited ARTN expression. Forced expression of ARTN decreased the sensitivity of HER2-positive mammary carcinoma cells to trastuzumab both in vitro and in vivo. Conversely, siRNA-mediated depletion of ARTN enhanced trastuzumab efficacy. Cells with acquired resistance to trastuzumab exhibited increased ARTN expression, the depletion of which restored trastuzumab sensitivity. Trastuzumab resistance produced an increased CSC population concomitant with enhanced mammospheric growth. ARTN mediated the enhancement of the CSC population by increased BCL-2 expression, and the CSC population in trastuzumab-resistant cells was abrogated upon inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells.
先前的研究表明，Artemin（ARTN）在乳腺癌中作为癌症干细胞（CSC）和转移因子发挥作用。在此，我们报告 ARTN 介导了曲妥珠单抗在 HER2 阳性乳腺癌细胞中的获得性耐药。增加 HER2 活性的配体增加了 HER2 阳性乳腺癌细胞中 ARTN 的表达，而曲妥珠单抗抑制了 ARTN 的表达。体外和体内强迫表达 ARTN 均降低了 HER2 阳性乳腺癌细胞对曲妥珠单抗的敏感性。相反，siRNA 介导的 ARTN 耗竭增强了曲妥珠单抗的疗效。对曲妥珠单抗产生获得性耐药的细胞表现出 ARTN 表达增加，耗尽 ARTN 可恢复曲妥珠单抗的敏感性。曲妥珠单抗耐药产生了一个增加的 CSC 群体，同时增强了乳腺球体生长。ARTN 通过增加 BCL-2 表达来介导 CSC 群体的增强，并且在抑制 BCL-2 后，曲妥珠单抗耐药细胞中的 CSC 群体被消除。因此，我们得出结论，ARTN 是 HER2 阳性乳腺癌细胞中曲妥珠单抗获得性耐药的一种介导物。
