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

Soojung Lee, Trine V Axelsen, Nicolai Jessen, Stine F Pedersen, Pernille Vahl, Ebbe Boedtkjer

Oncogene 2018 Oct

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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.

Citation

Soojung Lee, Trine V Axelsen, Nicolai Jessen, Stine F Pedersen, Pernille Vahl, Ebbe Boedtkjer. Na+,HCO3--cotransporter NBCn1 (Slc4a7) accelerates ErbB2-induced breast cancer development and tumor growth in mice. Oncogene. 2018 Oct;37(41):5569-5584