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Na+,HCO3–-cotransporter NBCn1 (Slc4a7) accelerates ErbB2-induced breast cancer development and tumor growth in mice

Oncogene volume 37, pages 5569–5584 (2018)Cite this article

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Abstract

Metabolic acid production challenges cellular pH homeostasis in solid cancer tissue, and mechanisms of net acid extrusion represent promising new targets for breast cancer therapy. Here, we used genetically engineered mice to investigate the contribution of the Na+,HCO3–-cotransporter NBCn1 (Slc4a7) to intracellular acid–base regulation in ErbB2-induced breast cancer tissue and the consequences of NBCn1 knockout for breast tumor development and growth. We demonstrate an approximately 2-fold increase of NBCn1 protein abundance in ErbB2-induced breast cancer tissue compared to normal breast tissue despite a 4-fold decrease in the NBCn1 mRNA level. In congruence, we show that NBCn1 facilitates net acid extrusion and elevates steady-state intracellular pH in breast cancer tissue. Disruption of NBCn1 expression delayed ErbB2-induced breast carcinogenesis from a median tumor-free survival of 9.5 months in wild-type mice to 12 months in NBCn1-knockout mice and decelerated the tumor growth rate by approximately 1/3. Glycolytic metabolism—evaluated based on the interstitial concentrations of lactate and glucose measured in microdialysates—was increased in breast cancer tissue compared to normal breast tissue, but was unaffected by NBCn1 knockout. Disruption of NBCn1 expression inhibited cell proliferation—evaluated by staining for the proliferative marker Ki67—particularly in central tumor areas with predicted increase in acid loading from glycolytic metabolism. In conclusion, NBCn1 regulates intracellular pH in ErbB2-induced breast cancer tissue by providing a pathway for cellular uptake of HCO3–, which can neutralize metabolic acidic waste products. Disrupting NBCn1 expression delays ErbB2-induced breast cancer development, inhibits cancer cell proliferation, and decelerates tumor growth.

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Acknowledgements

We thank Jane Rønn, Viola Larsen, and Katrine Mark for expert technical assistance.

Funding

This work was supported by the Danish Cancer Society (grant no. R42-A4273 to EB), the Novo Nordisk Foundation (grant no. NNF13OC0007393 and NNF15OC0017344 to EB and grant no. NNF16OC0023194 to SFP), and the Danish Council for Independent Research (grant no. 7025-00050B to EB).

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    Authors and Affiliations

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

      Soojung Lee, Trine V. Axelsen, Nicolai Jessen & Ebbe Boedtkjer

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

      Stine F. Pedersen

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

      Pernille Vahl

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    1. Soojung Lee
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    Correspondence to Ebbe Boedtkjer.

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    Ebbe Boedtkjer is inventor on patent applications related to data presented here. The other authors declare that they have no conflict of interest.

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    Lee, S., Axelsen, T.V., Jessen, N. et al. Na+,HCO3–-cotransporter NBCn1 (Slc4a7) accelerates ErbB2-induced breast cancer development and tumor growth in mice. Oncogene 37, 5569–5584 (2018). https://doi.org/10.1038/s41388-018-0353-6

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