Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
Int J Oncol. 2011 Dec;39(6):1501-9. doi: 10.3892/ijo.2011.1143. Epub 2011 Jul 26.
Multidrug resistance is the most predominant phenomenon leading to chemotherapy treatment failure in breast cancer patients. Despite many studies having suggested that overexpression of epidermal growth factor receptor (EGFR) is a potent predictor of malignancy in cancers, systematic research of EGFR in multidrug resistant (MDR) breast cancer cells is lacking. In order to clarify the role of EGFR in MDR breast cancer cells, MCF7/Adr expressing relatively higher EGFR, and its parental cell line MCF7 expressing relatively lower EGFR, were chosen for this study. Knockdown of EGFR by siRNA in MCF7/Adr cells showed that EGFR siRNA inhibits cell migration, invasion and proliferation in vitro; converse effects were observed in MCF7 cells transfected with pcDNA3.0-EGFR plasmid. Moreover, we found that EGFR upregulated migration and invasion via EMMPRIN, MMP2 and MMP9 in addition to promoting cell cycle passage via elevation of cyclin D1 and CDK4 in MDR breast cancer cells. Interestingly, MCF7/Adr cells not expressing EGFR showed significant decrease of P-glycoprotein (P-gp) and ABCG2 expression levels, and became more sensitive to treatment of adriamycin (ADR) and paclitaxel (Taxol); the above results indicated that MDR of cancer cells is related to S-phase arrest. In conclusion, EGFR is an important factor enhancing the malignancy of MDR breast cancer cells, partially, inducing MDR. Anti-EGFR therapy may improve outcome in chemorefractory breast cancer patients.
多药耐药性是导致乳腺癌患者化疗治疗失败的最主要现象。尽管许多研究表明表皮生长因子受体（EGFR）的过度表达是癌症恶性程度的一个有力预测指标，但 EGFR 在多药耐药（MDR）乳腺癌细胞中的系统研究却缺乏。为了阐明 EGFR 在 MDR 乳腺癌细胞中的作用，本研究选择了 EGFR 表达相对较高的 MCF7/Adr 及其亲本细胞系 MCF7/Adr 细胞。用 siRNA 敲低 MCF7/Adr 细胞中的 EGFR 表明，EGFR siRNA 抑制细胞迁移、侵袭和增殖；而在转染 pcDNA3.0-EGFR 质粒的 MCF7 细胞中则观察到相反的效果。此外，我们发现 EGFR 通过上调 EMMPRIN、MMP2 和 MMP9 促进迁移和侵袭，通过上调 cyclin D1 和 CDK4 促进细胞周期通过，从而增加了 MDR 乳腺癌细胞的迁移和侵袭。有趣的是，不表达 EGFR 的 MCF7/Adr 细胞显示出 P-糖蛋白（P-gp）和 ABCG2 表达水平的显著下降，并对阿霉素（ADR）和紫杉醇（Taxol）的治疗变得更加敏感；上述结果表明，癌细胞的多药耐药性与 S 期停滞有关。总之，EGFR 是增强 MDR 乳腺癌细胞恶性程度的重要因素，部分诱导 MDR。抗 EGFR 治疗可能改善化疗耐药性乳腺癌患者的预后。
