Acid-base transporters and ph dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival

Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pH_i) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na⁺,HCO₃^– cotransport and Na⁺/H⁺ exchange dominate cellular net acid extrusion in human breast carcinomas. Na⁺/H⁺ exchange elevates pH_i preferentially in estrogen receptor-negative breast carcinomas, whereas Na⁺,HCO₃^– cotransport raises pH_i more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na⁺/H⁺ exchanger NHE1/SLC9A1 and Na⁺,HCO₃^– cotransporter NBCn1/SLC4A7. Increased dependency on Na⁺,HCO₃^– cotransport associates with severe breast cancer: enlarged CO₂/HCO₃^–-dependent rises in pH_i predict accelerated cell proliferation, whereas enhanced CO₂/HCO₃^–-dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high SLC4A7 and/or low SLC9A1 mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na⁺,HCO₃^– cotransport for pH_i regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.