Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-α.
Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-α.
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DOI：
10.1038/onc.2011.483
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发表时间：
2012-07-05
期刊：
影响因子：
8
通讯作者：
Raman, V.
中科院分区：
文献类型：
--
作者：
Vesuna, F.;Lisok, A.;Kimble, B.;Domek, J.;Kato, Y.;van der Groep, P.;Artemov, D.;Kowalski, J.;Carraway, H.;van Diest, P.;Raman, V.
关键词：
雌激素受体α（ER）在乳腺癌发展中的作用以及作为乳腺癌预后的主要临床标志物已得到充分证实。在这项研究中，我们确定了致癌蛋白TWIST 1（Twist），它在高级别乳腺癌中过度表达，作为ER表达的潜在负调节因子。使用Twist低（MCF-7，T-47 D）和Twist高（Hs 578 T，MDA-MB-231，MCF-7/Twist）表达细胞系进行Twist对ER调节的功能表征。所有Twist高细胞系均表现出低ER转录物和蛋白水平。通过染色质免疫沉淀和启动子分析，我们证明Twist可以直接结合ER启动子中的E-box，并在体外显著下调ER启动子活性。在功能上，Twist过表达引起乳腺细胞的雌激素非依赖性增殖，并促进对选择性雌激素受体调节剂（SERM）他莫昔芬和选择性雌激素受体下调剂（SERD）氟维司群的激素抗性。重要的是，这种作用在下调Twist时是可逆的。此外，使用MCF-7/Twist细胞在小鼠中产生的原位肿瘤对他莫昔芬具有抗性。通过磁共振成像（MRI）确定，这些肿瘤具有高血管体积和渗透性表面积。从机制上讲，Twist将DNA甲基转移酶3B（DNMT 3B）募集到ER启动子，导致与亲本细胞相比ER启动子甲基化程度显著更高。此外，我们通过免疫共沉淀证明Twist与ER启动子处的组蛋白去乙酰化酶1（HDAC 1）相互作用，导致组蛋白去乙酰化和染色质浓缩，进一步降低ER转录水平。使用去甲基化剂5-氮杂胞苷和组蛋白去乙酰化酶抑制剂丙戊酸实现ER的功能性重新表达。最后，在人类乳腺肿瘤中观察到Twist和ER表达之间的反比关系。总之，Twist对ER的调节可能是乳腺肿瘤中观察到的ER活性丧失的潜在机制，并可能导致激素抵抗性ER阴性乳腺癌的产生。
The role of estrogen receptor alpha (ER) in breast cancer development and as a primary clinical marker for breast cancer prognosis is well documented. In this study, we identified the oncogenic protein TWIST1 (Twist), which is over-expressed in high-grade breast cancers, as a potential negative regulator of ER expression. Functional characterization of ER regulation by Twist was carried out using Twist low (MCF-7, T-47D) and Twist high (Hs 578T, MDA-MB-231, MCF-7/Twist) expressing cell lines. All Twist high cell lines exhibited low ER transcript and protein levels. By chromatin immunoprecipitation and promoter assays, we demonstrated that Twist could directly bind to E-boxes in the ER promoter and significantly down-regulate ER promoter activity in vitro. Functionally, Twist over-expression caused estrogen independent proliferation of breast cells and promoted hormone resistance to the selective estrogen receptor modulator (SERM) tamoxifen and selective estrogen receptor down-regulator (SERD) fulvestrant. Importantly, this effect was reversible on down-regulating Twist. Additionally, orthotopic tumors generated in mice using MCF-7/Twist cells were resistant to tamoxifen. These tumors had high vascular volume and permeability surface area as determined by magnetic resonance imaging (MRI). Mechanistically, Twist recruited DNA methyltransferase 3B (DNMT3B) to the ER promoter leading to a significantly higher degree of ER promoter methylation compared to parental cells. Furthermore, we demonstrated by co-immunoprecipitation that Twist interacted with histone deacetylase 1 (HDAC1) at the ER promoter, causing histone deacetylation and chromatin condensation, further reducing ER transcript levels. Functional re-expression of ER was achieved using demethylating agent 5-azacytidine and histone deacetylase inhibitor valproic acid. Finally, an inverse relationship was observed between Twist and ER expression in human breast tumors. In summary, the regulation of ER by Twist could be an underlying mechanism for loss of ER activity observed in breast tumors and may contribute to the generation of hormone resistant ER negative breast cancer.
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作者：
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影响因子：
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通讯作者：
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