PC cell-derived growth factor stimulates proliferation and confers trastuzumab resistance to Her-2-overexpressing breast cancer cells
PC cell-derived growth factor stimulates proliferation and confers trastuzumab resistance to Her-2-overexpressing breast cancer cells
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DOI：
10.1158/1078-0432.ccr-05-2663
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发表时间：
2006-07-15
影响因子：
11.5
通讯作者：
Serrero, Ginette
中科院分区：
文献类型：
--
作者：
Kim, Wes E.;Serrero, Ginette
目的：曲妥珠单抗仅对25%至30%的过度表达erbB 2/Her-2癌蛋白的乳腺癌患者有效。PC细胞衍生生长因子（PCDGF/GP 88）是一种88 kDa的糖蛋白生长因子，在80%的浸润性导管癌中过表达。我们的目的是确定PCDGF/GP 88水平的增加是否赋予erbB 2过表达的乳腺癌细胞中的曲妥珠单抗抗性。实验设计：在erbB 2过表达的MCF-7和SKBR 3乳腺癌细胞系中研究PCDGF诱导erbB 2磷酸化和赋予曲妥珠单抗抗性的能力。外源性PCDGF/GP 88以剂量依赖性和时间依赖性的方式诱导erbB 2过表达乳腺癌细胞中erbB 2的磷酸化。此外，PCDGF/GP 88的过表达在erbB 2过表达细胞中赋予曲妥珠单抗抗性。此外，在erbB 2过表达细胞中PCDGF/GP 88的过表达提供了相对于不具有增加的PCDGF/GP 88水平的erbB 2过表达细胞的生长优势。PCDGF/GP 88可诱导erbB 2高表达细胞丝裂原活化蛋白激酶磷酸化，且呈时间依赖性，曲妥珠单抗预处理不能降低PCDGF/GP 88诱导的丝裂原活化蛋白激酶磷酸化水平。结论：PCDGF/GP 88可使erbB 2高表达细胞产生曲妥珠单抗耐药。因此，PCDGF/GP 88水平的增加可能表明乳腺癌患者对曲妥珠单抗无反应。
Purpose: Trastuzumab is only effective in 25% to 30% of the administered breast cancer patients who overexpress the erbB2/Her-2 oncoprotein. PC cell - derived growth factor (PCDGF/GP88) is an 88-kDa glycoprotein growth factor overexpressed in 80% invasive ductal carcinomas. Our objective was to determine whether the increased levels of PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing breast cancer cells.Experimental Design: The ability of PCDGF to induce erbB2 phosphorylation and to confer Trastuzumab resistance was studied in erbB2-overexpressing MCF-7 and SKBR3 breast cancer cell lines.Results: PCDGF/GP88 added exogenously induced the phosphorylation of erbB2 in a dose-dependent and time-dependent manner in erbB2-overexpressing breast cancer cells. In addition, the overexpression of PCDGF/GP88 conferred Trastuzumab resistance in erbB2-overexpressing cells. Furthermore, overexpression of PCDGF/GP88 in erbB2-overexpressing cells provided a growth advantage over erbB2-overexpressing cells that do not have increased levels of PCDGF/GP88. Lastly, PCDGF/GP88 induced the phosphorylation of mitogen-activated protein kinase in a time-dependent manner in erbB2-overexpressing cells, and pretreatment with Trastuzumab was not able to attenuate the phosphorylation levels of mitogen-activated protein kinase induced by PCDGF/GP88.Conclusion: These data suggest that PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing cells. Thus, the increase in PCDGF/GP88 levels may indicate Trastuzumab unresponsiveness in breast cancer patients.