Kar Adwitiya, Liu Bolin, Gutierrez-Hartmann Arthur
Cancer Biology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, U.S.A.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, U.S.A.
Anticancer Res. 2017 Dec;37(12):6583-6591. doi: 10.21873/anticanres.12115.
BACKGROUND/AIM: ESE-1/Elf3 controls transformation properties in mammary epithelial cells, and is most clinically relevant in HER2 breast cancer. Herein we showed that ESE-1 knockdown inhibits tumorigenic growth in HER2, trastuzumab-resistant HR20 (derived from HER2 ER BT474) and Pool2 (derived from HER2 ER- SKBR3 cells) cell lines.
We used cell proliferation, clonogenicity, viability, and soft agar assays to measure the effects of ESE-1 knockdown in cell lines.
ESE-1 knockdown in the resistant cell lines inhibited HER2 and other downstream effectors in a cell-type specific manner, but caused down-regulation of pAkt and cyclin D1 in both sublines. In parental BT474 and SKBR3 ESE-1 silencing revealed a potent anti-proliferative effect that mimics the trastuzumab-mediated growth inhibition but did not enhance trastuzumab sensitivity in the resistant sublines.
This study provides rationale to study ESE-1 as a novel mean to treat HER2 patients who show resistance to anti-HER2 therapy.
背景/目的：ESE-1/Elf3调控乳腺上皮细胞的转化特性，在HER2乳腺癌中具有最大的临床相关性。在此我们表明，ESE-1基因敲低抑制HER2、曲妥珠单抗耐药的HR20（源自HER2雌激素受体阳性BT474细胞）和Pool2（源自HER2雌激素受体阴性SKBR3细胞）细胞系中的致瘤性生长。
我们使用细胞增殖、克隆形成、活力和软琼脂试验来测量ESE-1基因敲低对细胞系的影响。
耐药细胞系中的ESE-1基因敲低以细胞类型特异性方式抑制HER2及其他下游效应分子，但在两个亚系中均导致pAkt和细胞周期蛋白D1下调。在亲本BT474和SKBR3细胞中，ESE-1沉默显示出强大的抗增殖作用，模拟了曲妥珠单抗介导的生长抑制，但并未增强耐药亚系对曲妥珠单抗的敏感性。
本研究为将ESE-1作为治疗对抗HER2治疗耐药的HER2患者的新方法进行研究提供了理论依据。
