Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR.

// Yuan-Liang Wang 1 , Anne-Marie Overstreet 1 , Min-Shan Chen 1 , Jiang Wang 3 , Hua-Jun Zhao 1, 4 , Po-Chun Ho 1 , Molly Smith 1, 2 , Shao-Chun Wang 1, 2 1 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA 2 Cancer and Cell Biology Graduate Program, University of Cincinnati, Cincinnati, OH, USA 3 Department of Pathology & Lab Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA 4 School of Pharmacy, Zhejiang Chinese Medical University, Zhejiang, China Correspondence to: Shao-Chun Wang, e-mail: wangsc@ucmail.uc.edu Keywords: EGFR, c-ABL, lncRNA, b-catenin, breast cancer Received: September 28, 2014      Accepted: February 26, 2015      Published: March 10, 2015 ABSTRACT Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR ( HOX Antisense Intergenic RNA ). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.