TY - JOUR
T1 - Ablation of miR-10b suppresses oncogene-induced mammary tumorigenesis and metastasis and reactivates tumor-suppressive pathways
AU - Kim, Jongchan
AU - Siverly, Ashley N.
AU - Chen, Dahu
AU - Wang, Min
AU - Yuan, Yuan
AU - Wang, Yumeng
AU - Lee, Hyemin
AU - Zhang, Jinsong
AU - Muller, William J.
AU - Liang, Han
AU - Gan, Boyi
AU - Yang, Xianbin
AU - Sun, Yutong
AU - You, M. James
AU - Ma, Li
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - The invasive and metastatic properties of many human tumors have been associated with upregulation of the miRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here, we report the generation of miR-10b-deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR- 10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer. Among the target genes of miR-10b, the tumor suppressor genes Tbx5 and Pten and the metastasis suppressor gene Hoxd10 are significantly upregulated by miR-10b deletion. Mechanistically, miR-10b promotes breast cancer cell proliferation, migration, and invasion through inhibition of the expression of the transcription factor TBX5, leading to repression of the tumor suppressor genes DYRK1A and PTEN. In clinical specimens of breast cancer, the expression of TBX5, HOXD10, and DYRK1A correlates with relapse-free survival and overall survival outcomes in patients. Our results establish miR-10b as an oncomiR that drives metastasis, termed a metastamiR, and define the set of critical tumor suppressor mechanisms it overcomes to drive breast cancer progression.
AB - The invasive and metastatic properties of many human tumors have been associated with upregulation of the miRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here, we report the generation of miR-10b-deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR- 10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer. Among the target genes of miR-10b, the tumor suppressor genes Tbx5 and Pten and the metastasis suppressor gene Hoxd10 are significantly upregulated by miR-10b deletion. Mechanistically, miR-10b promotes breast cancer cell proliferation, migration, and invasion through inhibition of the expression of the transcription factor TBX5, leading to repression of the tumor suppressor genes DYRK1A and PTEN. In clinical specimens of breast cancer, the expression of TBX5, HOXD10, and DYRK1A correlates with relapse-free survival and overall survival outcomes in patients. Our results establish miR-10b as an oncomiR that drives metastasis, termed a metastamiR, and define the set of critical tumor suppressor mechanisms it overcomes to drive breast cancer progression.
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U2 - 10.1158/0008-5472.CAN-16-1571
DO - 10.1158/0008-5472.CAN-16-1571
M3 - Article
C2 - 27569213
AN - SCOPUS:84995685084
SN - 0008-5472
VL - 76
SP - 6424
EP - 6435
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -