MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells
MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells
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DOI：
10.1038/onc.2014.430
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发表时间：
2015-07-01
期刊：
影响因子：
8
通讯作者：
Zhang, C.
中科院分区：
文献类型：
--
作者：
Cui, J.;Yang, Y.;Zhang, C.
miRNAs（microRNAs）在许多癌症中频繁且异常地表达。MiR-873在结直肠癌和胶质母细胞瘤中表达下调。然而，其功能仍不清楚。在这里，我们报告了miR-873在乳腺肿瘤中的下调与正常组织相比。miR-873的增强表达通过调节ER阳性乳腺癌细胞中的ER α磷酸化降低ER（雌激素受体）-α而不是ER β的转录活性。我们还发现miR-873抑制乳腺癌细胞增殖和裸鼠肿瘤生长。报告基因分析显示细胞周期蛋白依赖性激酶3（CDK 3）是miR-873的直接靶点。CDK 3在乳腺癌中过表达，并在Ser 104/116和Ser 118磷酸化ER α。此外，我们发现Mir-873通过靶向CDK 3抑制ER活性和细胞生长。有趣的是，在他莫昔芬耐药MCF-7/TamR细胞中观察到miR-873下调，而CDK 3在这些细胞中过表达。更重要的是，miR-873的再表达逆转了MCF-7/TamR细胞中的他莫昔芬耐药性。我们的数据表明，miR-873是ER阳性乳腺癌的一种新型肿瘤抑制因子，也是治疗他莫昔芬耐药乳腺癌的一种潜在治疗方法。
miRNAs (microRNAs) are frequently and aberrantly expressed in many cancers. MiR-873 has been revealed to be downregulated in colorectal cancer and glioblastoma. However, its function remains unclear. Here we report that miR-873 is downregulated in breast tumor compared with normal tissue. Enforced expression of miR-873 decreases the transcriptional activity of ER (estrogen receptor)-alpha but not ER beta through the modulation of ER alpha phosphorylation in ER-positive breast cancer cells. We also found that miR-873 inhibits breast cancer cell proliferation and tumor growth in nude mice. Reporter gene assays revealed cyclin-dependent kinase 3 (CDK3) as a direct target of miR-873. CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERa at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3. Interestingly, miR-873 was observed to be downregulated in tamoxifen-resistant MCF-7/TamR cells, while CDK3 is overexpressed in these cells. More importantly, re-expression of miR-873 reversed tamoxifen resistance in MCF-7/TamR cells. Our data demonstrate that miR-873 is a novel tumor suppressor in ER-positive breast cancer and a potential therapeutic approach for treatment of tamoxifen-resistant breast cancer.