Abstract
Abstract The mechanisms behind the induction of stem cell properties by the epithelial to mesenchymal transition (EMT) remain largely undefined. Here we report the identification of the microRNA-146a (miR-146a) as a common target of the known EMT-inducers Krüppel-like factor 8 (KLF8) and TGF-β. Upon KLF8 overexpression or TGF-β treatment, a significant portion of the MCF-10A cells gained stem cell traits as demonstrated by an increase in the expression of CD44high/CD24low, the activity of aldehyde dehydrogenase (ALDH) and the mammosphere forming capability. Along with this change, the expression of miR-146a was highly upregulated in the cells. Consistently, we found that miR-146a was aberrantly co-overexpressed with KLF8 in a panel of invasive human breast cancer cell lines. Ectopic expression of KLF8 failed to induce the stem cell traits in the MCF-10A cells if the cells were pre-treated with miR-146a inhibitor, whereas overexpression of miR-146a in the MCF-10A cells alone was sufficient to induce the stem cell traits. Importantly, this induction of miR-146a-dependent stem traits by KLF8 was well correlated to the cell resistance to the cytotoxic effects of chemotherapeutic drugs such as paclitaxel. Co-staining and luciferase reporter analyses indicated that miR-146a targets the 3’-UTR of the Notch signaling inhibitor NUMB for translational inhibition. Overexpression of KLF8 dramatically potentiated the tumorigenecity of MCF-10A cells expressing the H-Ras oncogene, which was accompanied by a loss of NUMB expression in the tumors. Taken together, this study identifies a novel role and mechanism for KLF8 in inducing pro-tumorigenic mammary stemness and chemoresistance via miR-146a potentially by activating Notch signaling. This mechanism could be exploited as a therapeutic target against drug resisting breast cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A100. Citation Format: Xianhui Wang, Heng Lu, Tianshu Li, Lin Yu, Gang Liu, Xu Peng, Jihe Zhao. KLF8 induces breast stemness and chemoresistance via miRNAs associated with EMT. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A100.
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