Seven fulvestrant resistant cell lines derived from the estrogen receptor alpha positive MCF-7 human breast cancer cell line were used to investigate the importance of epidermal growth factor receptor (ErbB1-4) signaling. We found an increase in mRNA expression of EGFR and the ErbB3/ErbB4 ligand heregulin2 (hrg2) and a decrease of ErbB4 in all resistant cell lines. Western analyses confirmed the upregulation of EGFR and hrg2 and the downregulation of ErbB4. Elevated activation of EGFR and ErbB3 was seen in all resistant cell lines and the ErbB3 activation occurred by an autocrine mechanism. ErbB4 activation was observed only in the parental MCF-7 cells. The downstream kinases pAkt and pErk were increased in five of seven and in all seven resistant cell lines, respectively. Treatment with the EGFR inhibitor gefitinib preferentially inhibited growth and reduced the S phase fraction in the resistant cell lines concomitant with inhibition of Erk and unaltered Akt activation. In concert, inhibition of Erk with U0126 preferentially reduced growth of resistant cell lines. Treatment with ErbB3 neutralizing antibodies inhibited ErbB3 activation and resulted in a modest but statistically significant growth inhibition of two resistant cell lines. These data indicate that ligand activated ErbB3 and EGFR, and Erk signaling play important roles in fulvestrant resistant cell growth. Furthermore, the decreased level of ErbB4 in resistant cells may facilitate heterodimerization of ErbB3 with EGFR and ErbB2. Our data support that a concerted action against EGFR, ErbB2 and ErbB3 may be required to obtain complete growth suppression of fulvestrant resistant cells.

译文

:使用七种来自雌激素受体α阳性MCF-7人乳腺癌细胞的抗氟维司群抗性细胞系,调查表皮生长因子受体(ErbB1-4)信号传导的重要性。我们发现在所有耐药细胞系中EGFR和ErbB3 / ErbB4配体heregulin2(hrg2)的mRNA表达增加,而ErbB4的减少。 Western分析证实了EGFR和hrg2的上调以及ErbB4的下调。在所有耐药细胞系中均观察到EGFR和ErbB3的激活增强,并且ErbB3的激活是通过自分泌机制发生的。仅在亲本MCF-7细胞中观察到ErbB4激活。下游激酶pAkt和pErk在七个抗性细胞系中的五个中和在所有七个抗性细胞系中分别增加。用EGFR抑制剂吉非替尼治疗可优先抑制生长并降低耐药细胞系中的S期分数,同时抑制Erk和未改变的Akt激活。一致地,用U0126抑制Erk优先降低了抗性细胞系的生长。用ErbB3中和抗体处理可抑制ErbB3活化,并导致对两种抗性细胞系的抑制作用达到中等但统计学上显着的增长。这些数据表明配体激活的ErbB3和EGFR,以及Erk信号传导在耐氟司韦特的细胞生长中起重要作用。此外,耐药细胞中ErbB4水平降低可能有助于ErbB3与EGFR和ErbB2异源二聚化。我们的数据支持可能需要针对EGFR,ErbB2和ErbB3的协同作用才能获得对氟维司群抗性细胞的完全生长抑制。

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