Chen X, Yeung T K, Wang Z
Department of Cell Biology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
Biochem Biophys Res Commun. 2000 Nov 2;277(3):757-63. doi: 10.1006/bbrc.2000.3731.
Overexpression of ErbB2 has been found in approximately 25-30% of human breast cancers and has been shown to render the cancer cells more resistant to chemotherapy. However, it is not clear whether ErbB2 overexpression renders the cells more resistant to specific anti-cancer drugs or renders the cells more resistant to a broad range of anti-cancer drugs. It is not clear how the function of ErbB2 in drug resistance is related to expression and activation of the other ErbB receptors. In this communication, we showed that several breast cancer cell lines including BT20, BT474, MCF-7, MDA-MB-453, and SKBR-3 cells had a similar pattern of resistance to a broad range of anti-cancer drugs including 5-Fluorouracil, Cytoxan, Doxorubincin, Taxol, and Vinorelbin, suggesting a mechanism of multidrug resistance. High expression of P-glycoprotein and the ErbB receptors contribute to drug resistance of these breast cancer cells; however, overexpression of ErbB2 alone is not a major factor in determining drug resistance. To further determine the role of the ErbB receptors in drug resistance, we selected various NIH 3T3 cell lines that specifically expressed EGF receptor (EGFR), ErbB2, ErbB3, EGFR/ErbB2, EGFR/ErbB3, or ErbB2/ErbB3. A cytotoxicity assay showed that expression of ErbB2 alone did not significantly enhance drug resistance, whereas coexpression of either EGFR or ErbB3 with ErbB2 significantly enhanced drug resistance. Moreover, ErbB2 was highly phosphorylated in NIH 3T3 cells that coexpress ErbB2 with either EGFR or ErbB3, but not in NIH 3T3 cells that express ErbB2 alone. Together, our results suggest that coexpression of EGFR or ErbB3 with ErbB2 induces high phosphorylation of ErbB2 and renders the cells more resistant to various anti-cancer drugs.
在大约25%-30%的人类乳腺癌中发现了ErbB2的过表达，并且已表明其会使癌细胞对化疗更具抗性。然而，尚不清楚ErbB2过表达是使细胞对特定抗癌药物更具抗性，还是使细胞对广泛的抗癌药物更具抗性。也不清楚ErbB2在耐药性中的功能如何与其他ErbB受体的表达和激活相关。在本通讯中，我们表明包括BT20、BT474、MCF-7、MDA-MB-453和SKBR-3细胞在内的几种乳腺癌细胞系对包括5-氟尿嘧啶、环磷酰胺、多柔比星、紫杉醇和长春瑞滨在内的广泛抗癌药物具有相似的耐药模式，提示存在多药耐药机制。P-糖蛋白和ErbB受体的高表达促成了这些乳腺癌细胞的耐药性；然而，单独的ErbB2过表达并不是决定耐药性的主要因素。为了进一步确定ErbB受体在耐药性中的作用，我们选择了特异性表达表皮生长因子受体（EGFR）、ErbB2、ErbB3、EGFR/ErbB2、EGFR/ErbB3或ErbB2/ErbB3的各种NIH 3T3细胞系。细胞毒性试验表明，单独的ErbB2表达并未显著增强耐药性，而EGFR或ErbB3与ErbB2共表达则显著增强了耐药性。此外，在与EGFR或ErbB3共表达ErbB2的NIH 3T3细胞中，ErbB2高度磷酸化，但在单独表达ErbB2的NIH 3T3细胞中则没有。总之，我们的结果表明，EGFR或ErbB3与ErbB2共表达会诱导ErbB2的高度磷酸化，并使细胞对各种抗癌药物更具抗性。
