Androgens downregulate miR-21 expression in breast cancer cells underlining the protective role of androgen receptor.
Androgens downregulate miR-21 expression in breast cancer cells underlining the protective role of androgen receptor.
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DOI：
10.18632/oncotarget.7207
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Sisci D
中科院分区：
文献类型：
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作者：
Casaburi I;Cesario MG;Donà A;Rizza P;Aquila S;Avena P;Lanzino M;Pellegrino M;Vivacqua A;Tucci P;Morelli C;Andò S;Sisci D
虽然雄激素受体（AR）在乳腺癌（BC）中的保护作用已经确立，但其机制仍未被充分探讨。microrna在许多生物过程中发挥着重要作用，包括肿瘤细胞的发育和转移。在本文中，我们报道雄激素作为肿瘤mirna -21的负调节因子减少BC细胞的增殖。合成雄激素米boleron （Mib）降低miR-21过表达和AR敲低诱导的BC细胞增殖，证明AR在下调miR-21表达中的作用。这些影响似乎是发生在BC组织中的一般机制。染色质免疫沉淀（ChIP）分析揭示了AR与miR-21近端启动子中特定的ARE序列的结合，并识别出HDAC3的募集是AR介导的转录抑制的组成部分。这一事件与Mib处理提取物中PolII结合的显著降低有关，证实了活化的AR是miR-21表达的转录抑制因子，进一步深入了解雄激素在乳腺癌细胞中的保护作用。总的来说，我们的数据和AR在原发性和转移性乳腺肿瘤中的广泛表达，建议仔细检查雄激素的治疗潜力，以及增强抗雌激素辅助治疗的有效性。
Although the protective role of androgen receptor (AR) in breast cancer (BC) is well established, the mechanisms involved remains largely unexplored. MicroRNAs play fundamental roles in many biological processes, including tumor cell development and metastasis. Herein, we report that androgens reduce BC cells proliferation acting as a negative modulator of the onco-miRNA-21. The synthetic androgen miboleron (Mib) decreases BC cell proliferation induced by miR-21 over-expression and AR knockdown evidenced the requirement of AR in the down-regulation of miR-21 expression. These effects seem to be a general mechanism occurring in BC tissues. Chromatin immune-precipitation (ChIP) analysis disclosed the binding of AR to a specific ARE sequence in miR-21 proximal promoter and recognizes the recruitment of HDAC3 as component for AR-mediated transcriptional repression. Such event is associated to a significantly reduced PolII binding in Mib treated extracts confirming that activated AR is a transcriptional repressor of miR-21 expression, providing further insight into the protective role of androgens in breast cancer cells. Collectively, our data and the widespread AR expression in primary and metastatic breast tumours, suggest a careful examination of the therapeutic potential of androgens also in potentiating the effectiveness of anti-oestrogen adjuvant therapies.