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Disrupting Na+,HCO3–-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development

Oncogene volume 35, pages 2112–2122 (2016)Cite this article

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Abstract

Increased metabolism and insufficient blood supply cause acidic waste product accumulation in solid cancers. During carcinogenesis, cellular acid extrusion is upregulated but the underlying molecular mechanisms and their consequences for cancer growth and progression have not been established. Genome-wide association studies have indicated a possible link between the Na+,HCO3–-cotransporter NBCn1 (SLC4A7) and breast cancer. We tested the functional consequences of NBCn1 knockout (KO) for breast cancer development. NBCn1 protein expression increased 2.5-fold during breast carcinogenesis and was responsible for the increased net acid extrusion and alkaline intracellular pH of breast cancer compared with normal breast tissue. Genetic disruption of NBCn1 delayed breast cancer development: tumor latency was ~50% increased while tumor growth rate was ~65% reduced in NBCn1 KO compared with wild-type (WT) mice. Breast cancer histopathology in NBCn1 KO mice differed from that in WT mice and included less aggressive tumor types. The extracellular tumor microenvironment in NBCn1 KO mice contained higher concentrations of glucose and lower concentrations of lactate than that in WT mice. Independently of NBCn1 genotype, the cleaved fraction of poly(ADP-ribose) polymerase (PARP)-1 and expression of monocarboxylate transporter (MCT)1 increased while phosphorylation of Akt and ERK1 decreased as functions of tumor volume. Cell proliferation, evaluated from Ki-67 and phospho-histone H3 staining, was ~60% lower in breast cancer of NBCn1 KO than that of WT mice when corrected for variations in tumor size. We conclude that NBCn1 facilitates acid extrusion from breast cancer tissue, maintains the alkaline intracellular environment and promotes aggressive cancer development and growth.

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Acknowledgements

Financial support was provided from the Danish Council for Independent Research (10-094816 to EB and 12-127290 to SFP), Novo Nordisk Foundation (2131 and 7393 to EB), Danish Cancer Society (R72-A4273-13-S2 to EB) and MEMBRANES at Aarhus University. We thank Dr. Christian Aalkjaer (Aarhus University) for valuable discussions, Drs Frauke Alves and Roser Ufartes (Max Planck Institute for Experimental Medicine) for advice on chemical breast cancer induction and Dr Vibeke Dam, Jane Rønn and Ida Tvilling for expert technical assistance.

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  1. T V Axelsen and A P Andersen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    S Lee, T V Axelsen & E Boedtkjer

  2. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    A P Andersen & S F Pedersen

  3. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark

    P Vahl

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Correspondence to E Boedtkjer.

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Ebbe Boedtkjer is inventor on a patent application based on work described here. The other authors declare no conflict of interest.

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Lee, S., Axelsen, T., Andersen, A. et al. Disrupting Na+,HCO3–-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development. Oncogene 35, 2112–2122 (2016). https://doi.org/10.1038/onc.2015.273

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