Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin

// Cristine L. Chisholm 2, * , Haitao Wang 1, * , Ada Hang-Heng Wong 1 , Guelaguetza Vazquez-Ortiz 2 , Weiping Chen 3 , Xiaoling Xu 1 , Chu-Xia Deng 1, 2 1 Faculty of Health Sciences, University of Macau, Macau SAR, China 2 Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland MD, USA 3 Genomics Core Facility, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland MD, USA * These authors contributed equally to this work Correspondence to: Chu-Xia Deng, email: cxdeng@umac.mo Keywords: cisplatin, breast cancer, ATP7A, copper, resistance, sequestering Received: August 23, 2016 Accepted: October 12, 2016 Published: October 31, 2016 ABSTRACT Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors’ unique molecular adaptations.