Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer.

// Lichao Sun 1, 2, * , Joseph Burnett 1, * , Mari Gasparyan 1 , Fangying Xu 1 , Hui Jiang 3 , Chang-Ching Lin 1 , Ila Myers 1 , Hasan Korkaya 4 , Yajing Liu 5 , Jamie Connarn 1 , Huining He 6 , Ning Zhang 6 , Max S. Wicha 5 , Duxin Sun 1 1 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA 2 State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China 3 Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA 4 Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, 30912, USA 5 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA 6 College of Pharmacy and Tianjin Cancer Institute and Hospital, National Clinical Research Center of Cancer, Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China * These authors have contributed equally to this work Correspondence to: Duxin Sun, email: duxins@umich.edu Keywords: trastuzumab resistance, EMT, cancer stem cells, MEOX1, HER2+ breast cancer Received: January 11, 2016     Accepted: May 22, 2016     Published: June 06, 2016 ABSTRACT Continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-to-mesenchymal transition (EMT), transforms HER2+ to triple negative breast cancer, and expands breast cancer stem cells (BCSCs). Using cancer cell lines with two distinct states, epithelial and mesenchymal, we identified novel targets during EMT in PTEN-deficient trastuzumab-resistant breast cancer. Differential gene expression and distinct responses to a small molecule in BT474 (HER2+ trastuzumab-sensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) provided the selection tools to identify targets during EMT. siRNA knockdown and small molecule inhibition confirmed MEOX1 as one of the critical molecular targets to regulate both BCSCs and mesenchymal-like cell proliferation. MEOX1 was associated with poor survival, lymph node metastasis, and stage of breast cancer patients. These findings suggest that MEOX1 is a clinically relevant novel target in BCSCs and mesenchymal-like cancer cells in PTEN-deficient trastuzumab resistant breast cancer and may serve as target for future drug development.