目的：探讨雌激素受体β（estrogen receptor β，ERβ）的表达与乳腺癌他莫昔芬（tamoxifen，TAM）内分泌治疗耐药的相关性及其机制。方法：以前期构建的ERα/ERβ不同表达的人乳腺癌MCF-7细胞株\[M/HK（阴性对照）、M/siα（ERαlow/ERβhigh）、M/siβ（ERαhigh/ERβlow）细胞\]为研究对象，MTT法评估乳腺癌细胞对TAM的耐药性；用半定量RT-PCR法检测细胞中耐药相关基因MDR1、TOPOⅡ、LRP和GST-π的mRNA表达水平，用Western blotting法检测细胞中耐药相关信号通路MAPK、PI3K/Akt的p-ERK、p-Akt蛋白表达水平。结果：与对照组MCF-7细胞相比，MCF-7细胞中的ERβ高表达可促进高浓度TAM（1、5、10 μmol/L）对MCF-7细胞增殖的抑制作用\[（45.788 ± 1.641）% vs （24.288±1.170）%，（57.899±1.583）% vs（31.499±1.978）%，（59.853 ±1.648）% vs（38.039±1.482）%；均P<0.05 ）\]，该抑制作用与TAM浓度呈剂量依赖性。ERβ高表达可显著抑制MCF-7细胞耐药基因MDR1、TOPOⅡ、LRP的 mRNA表达水平（0.431±0.032 vs 0.932±0.083，0.234±0.008 vs 0.391±0.002，0.47±0.028 vs 0.586±0.036；均P<0.05)；可显著下调Akt和ERK蛋白的磷酸化水平（0224±0.006 vs 0.437±0.007，0.367±0.015 vs 0.756±0.039；均P<0.05)。结论： ERβ表达水平可影响乳腺癌细胞MCF-7对TAM的耐药性，该作用机制可能与耐药基因的表达及PI3K/ AKT、MAPK信号通路激活有关。

Objective: To investigate the relationship between the expression of estrogen receptorβand endocrine resistance to tamoxifen (TAM) in breast cancer. Methods: Human breast cancer MCF-7 cells transfected with ERα or ER β constructs, M/HK (negative control), M/siα (ERαhigh/ERβlow), and M/siβ (ERαhigh/ERβlow), respectively, were used. The resistance of these transfected cells to TAM was assessed by MTT assay, mRNA levels of the major drug-resistance related genes (MDR1, TOPOⅡ, LRP, and GST- π) by RT-PCR, and levels of p-Akt, p-ERK and PI3K/Akt (major components of the signaling pathways involved in drug-resistance) by Western blotting. Results: Compared with MCF-7 expressing M/HK, cells expressing ER βshowed enhanced proliferation inhibition mediated by TAM in a dose-dependent manner (P<0.05) : (45.788±1.641)% vs (24.288±1.170)% at 1 μmol/L， (57.899±1.583)% vs (31.499±1.978)% at 5 μmol/L, and (59.853±1.648)% vs (38.039±1.482)% at 10 μmol/L, had significantly lower (P<0.05) mRNA levels of MDR1 (0.431±0.032 vs 0.932±0.083), TOPOⅡ (0.234±0.008 vs 0.391±0.002), and LRP (0.47±0.028 vs 0.586±0.036), and had significantly decreased (P<0.05) levels of p-Akt (0.224±0.006) vs (0.437±0.007) and p-ERK (0.367±0.015 vs 0.756±0.039). Conclusion: ER β may alter the resistance of human breast cancer cells to TAM, possibly through down-regulating the expression of drug-resistance genes and activating PI3K/AKT and ERK signal pathways.

国家自然科学基金资助项目（No. 81273552，No.30901985）。