Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer

// Tianshu Li 1, 2 , Heng Lu 1 , Debarati Mukherjee 1 , Satadru K. Lahiri 1 , Chao Shen 1, 3 , Lin Yu 1 , Jihe Zhao 1 1 Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA 2 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA 3 College of Life Sciences, Wuhan University, Wuhan, China Correspondence to: 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 ABSTRACT 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.