Targeting lactate transport suppresses<i>in vivo</i>breast tumour growth

Abstract

// Filipa Morais-Santos 1, 2 , Sara Granja 1, 2 , Vera Miranda-Gon&ccedil;alves 1, 2 , Ant&oacute;nio H.J. Moreira 1, 2 , Sandro Queir&oacute;s 1, 2 , Jo&atilde;o L. Vila&ccedil;a 1, 2, 3 , Fernando C. Schmitt 4, 5, 6 , Adhemar Longatto-Filho 1, 2, 7, 8 , Joana Paredes 4 , F&aacute;tima Baltazar 1, 2, * , C&eacute;line Pinheiro 1, 2, 7, 9, * 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus of Gualtar, Braga, Portugal 2 ICVS/3B&rsquo;s - PT Government Associate Laboratory, Braga/Guimar&atilde;es, Portugal 3 DIGARC - Technology School, Polytechnic Institute of C&aacute;vado and Ave, Barcelos, Portugal 4 IPATIMUP - Institute of Molecular Pathology and Immunology of University of Porto, Porto, Portugal 5 Medical Faculty of the University of Porto, Porto, Portugal 6 Department of Pathology and Medicine, Laboratoire National de Sante, Dudelange, Luxembourg 7 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil 8 Laboratory of Medical Investigation (LIM-14), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil 9 Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, Sao Paulo, Brazil * These authors have contributed equally to this work Correspondence to: C&eacute;line Pinheiro, e-mail: celinepinheiro@gmail.com Keywords: monocarboxylate transporters, breast carcinoma, hypoxia, lactate, Warburg effect Received: January 21, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 04, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: May 14, 2015 ABSTRACT Background: Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as &ldquo;Warburg effect&rdquo;. Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment. Results: The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth. Conclusions: This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.