Yu D, Liu B, Jing T, Sun D, Price J E, Singletary S E, Ibrahim N, Hortobagyi G N, Hung M C
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Oncogene. 1998 Apr 23;16(16):2087-94. doi: 10.1038/sj.onc.1201729.
We recently found that overexpression of p185c-erbB2 in c-erbB2 transfected MDA-MB-435 breast cancer cells (435.eB transfectants) confers a 5-9-fold increase in Taxol resistance. To examine whether Taxol resistance is a common phenomenon in other c-erbB2 overexpressing breast cancer cell lines, we tested a panel of human breast cancer cell lines established from different patients and expressing pl85c-erbB2 at different levels for their sensitivity to Taxol and Taxotere, a synthetic taxoid. Higher expression of p185c-erbB2 in these breast cancer cell lines indeed correlated well with resistance to Taxol and Taxotere, and the degree of resistance was about 100-fold that in c-erbB2-overexpressing 435.eB transfectants, demonstrating that these breast cancer cells are highly resistant to Taxol. Since mdr-1-encoded p-glycoprotein (p170mdr-1) has been implicated in Taxol resistance, we next examined the p170mdr-1 levels in these breast cancer cell lines that are highly resistant to Taxol. Higher levels of p170mdr-1 expression were found in several breast cancer cell lines that are highly resistant to Taxol. Since these same breast cancer cell lines also expressed higher levels of p185c-erbB2, we sought to determine the relative contribution of p185c-erbB2 and p170mdr-1 overexpression to Taxol resistance. We first specifically down-regulated cell surface p185c-erbB2 using anti-p185c-erbB2 monoclonal antibodies and assayed sensitivity of these cells to Taxol. We next specifically inactivated p170mdr-1 function using p170mdr-1 blockers (thioridazine or verapamil) and again assayed Taxol sensitivity. Both p185c-erbB2 down-regulation and p170mdr-1 blockade significantly sensitized the breast cancer cell lines to Taxol. The results indicate that overexpression of either p185c-erbB2 or p170mdr-1 renders human breast cancer cells resistant to Taxol. Furthermore, p185c-erbB2 synergizes with p170mdr-1 conferring higher degrees of Taxol resistance. Finally, combination therapy (down-regulation of p185c-erbB2 plus blocking p170mdr-1 plus administration of Taxol) may be beneficial to breast cancer patients whose tumors express high levels of both p185c-erbB2 and p170mdr-1.
我们最近发现，在转染了c-erbB2的MDA-MB-435乳腺癌细胞（435.eB转染细胞）中p185c-erbB2的过表达使紫杉醇耐药性增加了5至9倍。为了研究紫杉醇耐药性在其他c-erbB2过表达的乳腺癌细胞系中是否是一种普遍现象，我们检测了一组从不同患者建立的、p185c-erbB2表达水平各异的人乳腺癌细胞系对紫杉醇和多西他赛（一种合成紫杉烷）的敏感性。这些乳腺癌细胞系中p185c-erbB2的高表达确实与对紫杉醇和多西他赛的耐药性密切相关，且耐药程度约为c-erbB2过表达的435.eB转染细胞的100倍，表明这些乳腺癌细胞对紫杉醇高度耐药。由于mdr-1编码的P-糖蛋白（p170mdr-1）与紫杉醇耐药性有关，我们接下来检测了这些对紫杉醇高度耐药的乳腺癌细胞系中的p170mdr-1水平。在几个对紫杉醇高度耐药的乳腺癌细胞系中发现了较高水平的p170mdr-1表达。由于这些相同的乳腺癌细胞系也表达较高水平的p185c-erbB2，我们试图确定p185c-erbB2和p170mdr-1过表达对紫杉醇耐药性的相对贡献。我们首先使用抗p185c-erbB2单克隆抗体特异性下调细胞表面的p185c-erbB2，并检测这些细胞对紫杉醇的敏感性。接下来，我们使用p170mdr-1阻滞剂（硫利达嗪或维拉帕米）特异性灭活p170mdr-1的功能，并再次检测紫杉醇敏感性。p185c-erbB2的下调和p170mdr-1的阻断均显著使乳腺癌细胞系对紫杉醇敏感。结果表明，p185c-erbB2或p170mdr-1的过表达均可使人乳腺癌细胞对紫杉醇产生耐药性。此外，p185c-erbB2与p170mdr-1协同作用，赋予更高程度的紫杉醇耐药性。最后，联合治疗（下调p185c-erbB2加阻断p170mdr-1加给予紫杉醇）可能对肿瘤同时高表达p185c-erbB2和p170mdr-1的乳腺癌患者有益。
