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首页> 外文期刊>Journal of Cancer Research and Treatment >Presence of Lamin A is Required for GATA3 and ERα Downregulation by Histone Deacetylase Inhibitor in Breast Cancer Cells
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Presence of Lamin A is Required for GATA3 and ERα Downregulation by Histone Deacetylase Inhibitor in Breast Cancer Cells

机译：组蛋白去乙酰化酶抑制剂抑制乳腺癌细胞中GATA3和ERα下调需要Lamin A的存在

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Background: Breast cancer treatment is challenging due to the inconsistence in tumour biomarker expression including progesterone receptor (PR), estrogen receptor-α (ERα) and GATA3 transcription factor. GATA3 has role in epithelial cell differentiation along with nuclear envelope protein lamin A. The breast cancer cell line MCF7 expresses ERα, abnormal GATA3 isoforms, low PR but lacks lamin A. MCF7 cells are resistant to tamoxifen targeting ERα and more anticancer drugs are being studied to kill them. One of the mechanisms surrounding breast cancer initiation is histone deacetylation. Our objective is to investigate the effect of histone deacetylase inhibitor (HDACI) on PR, ERα and GATA3 expression along with the induction of apoptosis in MCF7 cells forced expressing lamin A. Subsequently, they are also explored as biomarkers for breast cancer prognostic and indicators for targeted breast cancer therapy. Methods: The HDACI used here is Suberoyl-Bis-Hydroxamic Acid (SBHA). Western blot was used to analyze the expression of PR, ERα, and GATA3 in MCF7 control transfected with histone H2B-GFP (MCF7-H2B-GFP) and in MCF7 transfected with lamin A-RFP (MCF7-LA-RFP). The analyses were carried out before and after treatment with DMSO (mock) or SBHA (1 or 2 μM) for 12h. The in vivo expression of the PR, ERα and GATA3 were also explored in 36 archived cell lysates derived from breast cancer micro-biopsies. Results: MCF7-H2B-GFP treated with SBHA increased PR, ERα while MCF7-LA-RFP treated with SBHA reduced ERα and GATA3 but not PR. Biomarkers analysis in ductal carcinoma micro-biopsies derived samples showed that 30% had lost lamin A while 64% expressed PR, ERα and GATA3. Conclusion: In presence of lamin A, SBHA downregulated cancer initiators GATA3 and ERα while inducing cell death. These biomarkers could be useful molecular tools prior to initiating targeted breast cancer therapy.
机译：背景：由于包括孕激素受体（PR），雌激素受体-α（ERα）和GATA3转录因子在内的肿瘤生物标志物表达的不一致，乳腺癌的治疗具有挑战性。 GATA3与核被膜蛋白Lamin A一起在上皮细胞分化中起作用。乳腺癌细胞系MCF7表达ERα，GATA3亚型异常，PR低但缺乏LaminA。MCF7细胞对他莫昔芬靶向ERα有抗性，并且正在研究更多的抗癌药物杀死他们乳腺癌引发的机制之一是组蛋白脱乙酰化。我们的目的是研究组蛋白脱乙酰基酶抑制剂（HDACI）对PR，ERα和GATA3表达的影响，以及诱导强迫表达层粘连蛋白A的MCF7细胞凋亡的作用。随后，它们也被用作乳腺癌预后的生物标志物和指标针对性的乳腺癌治疗。方法：此处使用的HDACI为Suberoyl-Bis-羟氨基甲酸（SBHA）。 Western印迹用于分析PR，ERα和GATA3在组蛋白H2B-GFP（MCF7-H2B-GFP）转染的MCF7对照和层粘连蛋白A-RFP（MCF7-LA-RFP）转染的MCF7中的表达。在用DMSO（模拟物）或SBHA（1或2μM）处理12小时之前和之后进行分析。 PR，ERα和GATA3的体内表达也在36种源自乳腺癌微活检组织的细胞裂解物中进行了探索。结果：SBHA处理的MCF7-H2B-GFP增加PR，ERα，而SBHA处理的MCF7-LA-RFP减少ERα和GATA3，但不减少PR。在导管癌显微活检样本中进行的生物标记分析显示，有30％的人失去了层粘连蛋白A，而64％的人表达了PR，ERα和GATA3。结论：在层粘连蛋白A的存在下，SBHA在诱导细胞死亡的同时下调了癌症引发剂GATA3和ERα的表达。在启动靶向乳腺癌治疗之前，这些生物标记物可能是有用的分子工具。

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