Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424-503 Gene Cluster
Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424-503 Gene Cluster
复制标题
乳腺癌细胞的转移异质性与异质 TGF beta 激活 miR424-503 基因簇的表达相关
DOI：
10.1158/0008-5472.can-14-0389
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
Li, Yun;Li, Wei;Li, Mengfeng
TGF beta signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGF beta activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGF beta signaling can be over-activated and sustained. To better understand how the TGF beta inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424-503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGF beta signaling, leading to enhanced TGF beta signaling and metastatic capability of breast cancer cells. Moreover, antagonizing miR424-503 in breast cancer cells suppressed metastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424-503 cluster contributed to the heterogeneity of TGF beta activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novel mechanism, mediated by elevated expression of the miR424-503 cluster, underlying TGF beta activation and metastasis of human breast cancer. (C) 2014 AACR.
