Estrogen receptor α regulates ATM Expression through miRNAs in breast cancer.
Estrogen receptor α regulates ATM Expression through miRNAs in breast cancer.
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DOI：
10.1158/1078-0432.ccr-12-3700
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Guo X;Yang C;Qian X;Lei T;Li Y;Shen H;Fu L;Xu B
雌激素受体α（ERα）是调节乳腺发育的重要因子，与乳腺癌的发生、发展密切相关。大多数ER阴性乳腺癌表现出更具侵袭性的临床行为，并且对抗雌激素治疗具有抗性。此外，许多ER阴性肿瘤对许多化疗药物和放射治疗不敏感，尽管这种表型的机制尚不清楚。我们用多种抗体对296例乳腺癌组织进行了免疫组化。本研究在临床资料的基础上，利用siRNA技术，研究ERα对乳腺癌细胞系ATM表达的影响。此外，我们使用针对miRNA或miRNA过表达质粒的反义寡核苷酸来研究miRNA 18 a和106 a对ATM表达的作用。最后，我们采用原位杂交技术来评估乳腺癌组织中miRNA 18 a和106 a的表达。我们发现，在ER阴性乳腺癌组织中，ATM激酶（一种关键的DNA损伤反应蛋白）的表达异常上调。我们还发现放疗后局部复发率与ATM表达呈正相关。在细胞水平上，我们证明了ERα，而不是ERβ，负调控ATM表达。此外，我们发现ERα激活miRNA-18 a和106 a下调ATM表达。我们还证明了miRNA-18 a和106 a在ER阴性乳腺癌组织中显著低表达。我们揭示了一种新的机制，涉及ERα和miRNA 18 a和106 a调控ATM在乳腺癌中的作用。
Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER negative breast cancers display more aggressive clinical behaviors and are resistant to anti-estrogen therapies. In addition, many ER negative tumors show insensitivity to many chemotherapeutic drugs and radiation therapy, although mechanisms underlying this phenotype are less clear. We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. Based on the clinical data, we performed siRNA knock-down to study the role of ERα on ATM expression in breast cancer cell lines. Further we used antisense oligonucleotides against miRNAs or miRNA overexpression plasmids to study the role of miRNA 18a and 106a on ATM expression. Finally we employed in situ hybridization to assess miRNA 18a and 106a expression in breast cancer tissues. We found that in ER negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage response protein, is aberrantly up-regulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we demonstrated that ERα, but not ERβ, negatively regulates ATM expression. Furthermore, we identified that ERα activates miRNA- 18a and 106a to down-regulate ATM expression. We also demonstrated that miRNA-18a and 106a were significantly under-expressed in ER negative breast cancer tissues. We reveal a novel mechanism involving ERα and miRNA 18a and 106a regulation of ATM in breast cancer.