Associação Portuguesa de Investigação em Cancro
Targeting lactate transport suppresses in vivo breast tumour growth
Targeting lactate transport suppresses in vivo breast tumour growth
Production of lactate is one of the main features of tumours, promoting acidification of tumour microenvironment and consequently increases tumoral growth. In this way, several studies of our group have reported the inhibition of lactate transporters (MCTs) which promotes the inhibition of lactate transport to cell outside, inducing cell death. Thus, in this study MCT1 and MCT4 gene was silenced in human breast cancer cells, which induced a decrease in cell proliferation, migration and invasion. Also, silencing of MCTs in mouse xenografts decreased tumoural growth, and importantly some of the experimental groups have not formed tumours. The results obtained here support targeting of lactate transport as a strategy to treat breast cancer, with a special emphasis to the basal like subtype which so far does not have a specific molecular therapy.
Authors and Affiliations:
Filipa Morais-Santos1,2, Sara Granja1,2, Vera Miranda-Gonçalves1,2, António H.J. Moreira1,2, Sandro Queirós1,2, João L. Vilaça1,2,3, Fernando C. Schmitt 4,5,6, Adhemar Longatto-Filho1,2,7,8, Joana Paredes3, Fátima Baltazar1,2,* and Céline Pinheiro1,2,7,*
1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus of Gualtar, Braga, Portugal
2 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
3 DIGARC- Technology School, Polytechnic Institute of Cávado 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, 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
*(F Baltazar and C Pinheiro contributed equally to this work)
Abstract:
Background: Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as “Warburg effect”. 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.
Journal: Oncotarget
