A Her2-let-7-β2-AR circuit affects prognosis in patients with Her2-positive breast cancer.
A Her2-let-7-β2-AR circuit affects prognosis in patients with Her2-positive breast cancer.
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Her2-let-7-β2-AR 回路影响 Her2 阳性乳腺癌患者的预后
DOI：
10.1186/s12885-015-1869-6
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发表时间：
2015-11-02
期刊：
影响因子：
3.8
通讯作者：
Shi M
中科院分区：
文献类型：
--
作者：
Liu D;Deng Q;Sun L;Wang T;Yang Z;Chen H;Guo L;Liu Y;Ma Y;Guo N;Shi M
我们前期的研究表明β2-肾上腺素能受体（β2-AR）在大多数Her 2过表达的乳腺癌中高度表达。然而，在Her 2过表达的乳腺癌细胞中β2-AR表达上调的潜在机制尚未完全了解。乳腺癌中β2-AR过表达的临床意义尚不清楚。用let-7模拟物或抑制剂转染人乳腺癌细胞MCF-7和MCF-7/Her 2。Western blot检测β2-AR的表达。采用免疫组化方法检测乳腺癌原发灶、转移灶及49例乳腺癌原发灶和50例转移淋巴结组织芯片中β2-AR的表达。在Her 2阳性乳腺癌患者的59例原发性肿瘤组织中确定了淋巴结转移与β2-AR水平的相关性。采用回顾性研究方法，评价β2-AR过表达在Her 2阳性乳腺癌患者中的临床预后意义。Her 2过表达的乳腺癌细胞SKBR 3和BT474中的let-7 f水平显著低于表达低水平Her 2的MCF-7细胞。Her 2在MCF-7细胞中的异位表达（MCF-7/Her 2）抑制microRNA let-7 f的表达，其先前被鉴定为调节基线β2-AR表达。用MEK 1/2抑制剂PD 98059或PD 184352处理有效地恢复了let-7 f水平，表明Her 2过表达介导的ERK组成性激活抑制了let-7 f，导致β2-AR表达上调。let-7 f模拟物转染显著下调亲本MCF-7和MCF-7/Her 2细胞中β 2-AR的表达，而let-7抑制剂显著上调亲本MCF-7和MCF-7/Her 2细胞中β2-AR的表达。此外，用异丙肾上腺素处理MCF-7/Her 2细胞导致let-7 f表达的浓度依赖性降低，表明Her 2过表达对let-7 f的抑制作用可以通过激动剂触发的β2-AR激活来加强。我们进一步证实β2-AR高水平与Her 2阳性乳腺癌患者的淋巴结转移和不良预后相关。Her 2、β2-AR和let-7 f之间的相互作用可能维持乳腺癌细胞中高水平的β2-AR。我们的数据表明，β2-AR可能是一个新的有用的生物标志物，用于预测Her 2阳性乳腺癌的预后，也可能是一个有前途的选择性治疗靶点，用于乳腺癌的侵袭亚型。本文的在线版本（doi：10.1186/s12885-015-1869-6）包含补充材料，可供授权用户使用。
Our previous studies show that β2-adrenergic receptor (β2-AR) is highly expressed in most Her2-overexpressing breast cancers. However, the mechanisms underlying upregulation of the β2-AR expression in Her2-overexpressing breast cancer cells are not fully understood. The clinical significance of the β2-AR overexpression in breast cancer is unclear. Human breast cancer cells MCF-7 and MCF-7/Her2 were transfected with the let-7 mimics or inhibitors. The expression of β2-AR was analyzed by Western blot. The β2-AR status in primary and metastatic sites of breast cancer and the human breast cancer tissue microarrays containing 49 primary tumors and 50 metastatic lymph node tissues was analyzed by immunohistochemistry. The correlation of lymph node metastasis with the β2-AR level was determined in 59 primary tumor tissues from the patients with Her2-positive breast cancer. The clinical prognostic significance of the β2-AR overexpression in the patients with Her2-positive breast cancers was evaluated by a retrospective study. The let-7f level in Her2-overexpressing breast cancer cells SKBR3 and BT474 was significantly lower than that in MCF-7 cells, which express low level of Her2. Ectopic expression of Her2 in MCF-7 cells (MCF-7/Her2) represses the expression of microRNA let-7f, which is previously identified to regulate baseline β2-AR expression. The treatment with MEK1/2 inhibitors PD98059 or PD184352 effectively restored the let-7f level, suggesting that Her2-overexpression-mediated ERK constitutive activation inhibited let-7f, leading to the upregulation of the β2-AR expression. The transfection with the let-7f mimics markedly downregulated the β2-AR level, whereas the let-7 inhibitor significantly upregulated the β2-AR expression in both parental MCF-7 and MCF-7/Her2 cells. In addition, treatment of MCF-7/Her2 cells with isoproterenol resulted in a concentration-dependent reduction of the let-7f expression, demonstrating that the inhibitory effect of Her2 overexpression on let-7f can be reinforced by agonist-triggered β2-AR activation. We further demonstrate that high level of β2-AR associates with lymph node metastasis and poor outcome in the patients with Her2-positive breast cancer. The mutual and reciprocal interaction between Her2, β2-AR, and let-7f may maintain a high level of β2-AR in breast cancer cells. Our data suggest that β2-AR may be a new useful biomarker for predicting prognosis in Her2-positive breast cancer and may also be a promising selective therapeutic target for the aggressive subtype of breast cancer. The online version of this article (doi:10.1186/s12885-015-1869-6) contains supplementary material, which is available to authorized users.