Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells

// Ming Zhao 1 , Erin W. Howard 1 , Amanda B. Parris 1 , Zhiying Guo 1 , Qingxia Zhao 1, 2 , Zhikun Ma 1 , Ying Xing 2 , Bolin Liu 3 , Susan M. Edgerton 3 , Ann D. Thor 3 and Xiaohe Yang 1, 4 1 Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biological and Biomedical Sciences, North Carolina Central University, Kannapolis, North Carolina, USA 2 Basic Medical College of Zhengzhou University, Zhengzhou, Henan, P.R. China 3 Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA 4 College of Medicine, Henan University of Sciences and Technology, Luoyang, Henan, P.R. China Correspondence to: Xiaohe Yang, email: xyang@nccu.edu Keywords: CIP2A, lapatinib resistance, ErbB2, breast cancer, PP2A Received: November 05, 2016      Accepted: July 11, 2017      Published: July 19, 2017 ABSTRACT Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer. Our study investigated the role of CIP2A in the anti-cancer efficacy of lapatinib in ErbB2-overexpressing breast cancer cells. We found that lapatinib concurrently downregulated CIP2A and receptor tyrosine kinase signaling in ErbB2-overexpressing SKBR3 and 78617 cells; however, these effects were attenuated in lapatinib-resistant (LR) cells. CIP2A overexpression rendered SKBR3 and 78617 cells resistant to lapatinib-induced apoptosis and growth inhibition. Conversely, CIP2A knockdown via lentiviral shRNA enhanced cell sensitivity to lapatinib-induced growth inhibition and apoptosis. Results also suggested that lapatinib downregulated CIP2A through regulation of protein stability. We further demonstrated that lapatinib-induced CIP2A downregulation can be recapitulated by LY294002, suggesting that Akt mediates CIP2A upregulation. Importantly, lapatinib induced differential CIP2A downregulation between parental BT474 and BT474/LR cell lines. Moreover, CIP2A shRNA knockdown significantly sensitized the BT474/LR cells to lapatinib. Collectively, our results demonstrate that CIP2A is a molecular target and resistance factor of lapatinib with a critical role in lapatinib-induced cellular responses, including the inhibition of the CIP2A-Akt feedback loop. Further investigation of lapatinib-mediated CIP2A regulation will advance our understanding of lapatinib-associated anti-tumor activities and drug resistance.