Na+,HCO3−‐cotransport is crucial for intracellular pH control in human breast cancer

Abstract

Single nucleotide polymorphisms in Na+,HCO3−‐cotransporter NBCn1 (SLC4A7) are associated with breast cancer. Here, we studied the expression of NBCn1 and the importance of Na+,HCO3− ‐cotransport in human and mouse breast carcinomas. NBCn1 expression was detected at mRNA‐ and protein level in freshly obtained human breast tumors. Immunohistochemical membrane staining for NBCn1 was increased in human primary breast carcinomas and metastases compared to matched healthy breast epithelium. Using pH‐sensitive fluorophores, we found that Na+,HCO3 −‐cotransport and Na+/H+‐exchange are the only important mechanisms of net acid extrusion from human and ErbB2‐overexpressing mouse primary breast carcinomas. In the near‐physiological pHi range (pHi>6.60), CO2/HCO3−‐dependent mechanisms were responsible for >90% of total net acid extrusion. Steady‐state pHi of human breast carcinomas was 0.35±0.06 units lower in the absence than in the presence of CO2/HCO3−. In conclusion, NBCn1 expression is increased in human breast carcinomas where Na+,HCO3−‐cotransport is a prominent mechanism of acid extrusion and crucial for steady‐state pHi control. Support: Danish Council for Independent Research and Danish Cancer Society.