Na⁺,HCO₃^- cotransporter NBCn1 accelerates breast carcinogenesis

Cell metabolism increases during carcinogenesis. Yet, intracellular pH in solid cancer tissue is typically maintained equal to or above that of normal tissue. This is achieved through accelerated cellular acid extrusion that compensates for the enhanced metabolic acid production. Upregulated Na⁺,HCO₃^- cotransport is the predominant mechanism of net acid extrusion in human and murine breast cancer tissue, and in congruence, the protein expression of the electroneutral Na⁺,HCO₃^- cotransporter NBCn1 is increased in primary breast carcinomas and lymph node metastases compared to matched normal breast tissue. The capacity for net acid extrusion and level of steady-state intracellular pH are lower in carcinogen- and ErbB2-induced breast cancer tissue from NBCn1 knockout mice compared to wild-type mice. Consistent with importance of intracellular pH control for breast cancer development, tumor-free survival is prolonged and tumor growth rate decelerated in NBCn1 knockout mice compared to wild-type mice. Glycolytic activity increases as function of tumor size and in areas of poor oxygenation. Because cell proliferation in NBCn1 knockout mice is particularly reduced in larger-sized breast carcinomas and central tumor regions with expected hypoxia, current evidence supports that NBCn1 facilitates cancer progression by eliminating intracellular acidic waste products derived from cancer cell metabolism. The present review explores the mechanisms and consequences of acid-base regulation in breast cancer tissue. Emphasis is on the Na⁺,HCO₃^- cotransporter NBCn1 that accelerates net acid extrusion from breast cancer tissue and thereby maintains intracellular pH in a range permissive for cell proliferation and development of breast cancer.