Different epigenetic mechanisms of ERα implicated in the fate of fulvestrant-resistant breast cancer
Different epigenetic mechanisms of ERα implicated in the fate of fulvestrant-resistant breast cancer
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DOI：
10.1016/j.jsbmb.2016.11.017
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发表时间：
2017-03-01
影响因子：
4.1
通讯作者：
Hayashi, Shin-ichi
中科院分区：
文献类型：
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作者：
Tsuboi, Kouki;Kaneko, Yosuke;Hayashi, Shin-ichi
大约70%的乳腺癌表达雌激素受体α(ERα)，它在乳腺癌的发生发展中起着关键作用。氟维斯特已被有效地用于治疗ERα阳性乳腺癌，尽管耐药性仍然是一个关键问题。为了阐明其耐药机制，我们从ERα阳性的乳腺癌细胞株MCF-7和T-47D分别建立了耐药细胞系MFR(MCF-7派生的弗维斯特耐药)和TFR(T-47D派生的弗维斯特耐药)。两种对氟维斯特耐药的细胞株都对雌激素和抗雌激素失去敏感性。我们观察到ERα在蛋白质和mRNA水平上的表达减弱。为了探讨基因表达调控的机制，我们研究了表观遗传改变，特别是Era基因启动子的DNA甲基化水平。MFR细胞显示ERα基因上游的甲基化水平很高，而TFR细胞中没有观察到DNA甲基化的变化。因此，我们检测了ERα基因表达的可塑性，因为在停药后其可逆性存在差异。在MFR细胞中，ERα基因的表达没有恢复，细胞内交替的磷酸化信号被激活。相反，TFR细胞表现出ERα基因表达的可塑性和ERα依赖的生长；此外，这些细胞对雌激素和抗雌激素重新敏感。不同细胞间表观遗传调控的差异可能解释了ERα表达可塑性的差异。我们还发现了一个激活MFR细胞的HER/Src-Akt/MAPK通路；因此，特异性的抑制剂有效地抑制了MFR细胞的生长。这一发现暗示了多种福维斯特耐药机制的存在，并表明由于调控ERα基因表达的表观遗传机制的不同，不同肿瘤的最佳治疗方案也不同。(C)2016爱思唯尔有限公司。保留所有权利。
Approximately 70% of breast cancers express estrogen receptor a. (ER alpha), which plays critical roles in breast cancer development. Fulvestrant has been effectively used to treat ER alpha-positive breast cancer, although resistance remains a critical problem. To elucidate the mechanism of resistance to fulvestrant, we established fulvestrant-resistant cell-lines named MFR (MCF-7 derived fulvestrant resistance) and TFR (T-47D derived fulvestrant resistance) from the ER alpha-positive luminal breast cancer cell lines MCF-7 and T-47D, respectively. Both fulvestrant-resistant cell lines lost sensitivity to estrogen and anti estrogens. We observed diminished ER alpha expression at both the protein and mRNA levels. To address the mechanism of gene expression regulation, we examined epigenetic alteration, especially the DNA methylation level of ERa gene promoters. MFR cells displayed high methylation levels upstream of the ER alpha gene, whereas no change in DNA methylation was observed in TFR cells. Hence, we examined the gene expression plasticity of ER alpha, as there are differences in its reversibility following fulvestrant withdrawal. ER alpha gene expression was not restored in MFR cells, and alternative intracellular phosphorylation signals were activated. By contrast, TFR cells exhibited plasticity of ER alpha gene expression and ER alpha-dependent growth; moreover, these cells were resensitized to estrogen and anti estrogens. The difference in epigenetic regulation among individual cells might explain the difference in the plasticity of ER alpha expression. We also identified an MFR cell-activating HER/Src-Akt/MAPK pathway; thus, the specific inhibitors effectively blocked MFR cell growth. This finding implies the presence of multiple fulvestrant resistance mechanisms and suggests that the optimal therapies differ among individual tumors as a result of differing epigenetic mechanisms regulating ER alpha gene expression. (C) 2016 Elsevier Ltd. All rights reserved.