Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer
Metrics: PDF 1279 views | HTML 1565 views | ?
Tianshu Li1,2, Heng Lu1, Debarati Mukherjee1, Satadru K. Lahiri1, Chao Shen1,3, Lin Yu1, Jihe Zhao1
1Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA
2Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
3College of Life Sciences, Wuhan University, Wuhan, China
Jihe Zhao, e-mail: Jihe.Zhao@ucf.edu
Keywords: KLF8, EGFR, microRNA141, invasion and metastasis, breast cancer
Received: March 17, 2015 Accepted: May 14, 2015 Published: May 27, 2015
Krüppel-like factor 8 (KLF8) is a dual transcriptional factor critical for breast cancer progression. Epidermal growth factor receptor (EGFR) is frequently overexpressed in aggressive such as triple-negative breast cancer and associated with poor clinical outcomes. Here we report a novel KLF8-EGFR signaling axis in breast cancer. We identified a highly correlated co-overexpression between KLF8 and EGFR in invasive breast cancer cells and patient tumor samples. Overexpression of KLF8 in the non-tumorigenic MCF-10A cells induced the expression of EGFR, whereas knockdown of KLF8 from the MDA-MB-231 cells decreased it. Promoter activation and binding assays indicated that KLF8 promotes the EGFR expression by directly binding its gene promoter. We also revealed that KLF8 directly represses the promoter of miR141 and miR141 targets the 3′-untranslational region of EGFR transcript to inhibit EGFR translation. Treatment with the EGFR inhibitor AG1478 or overexpression of miR141 blocked the activity of ERK downstream of EGFR and inhibited KLF8-depndent cell invasiveness, proliferation and viability in cell culture and invasive growth and lung metastasis in nude mice. Conversely, overexpression of an inhibitory sponge of miR141 led to the opposite phenotypes. Taken together, these findings demonstrate a novel KLF8 to miR141/EGFR signaling pathway potentially crucial for breast cancer malignancy.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.