ABSTRACT
Aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. This is likely in concert with the ion transport family. Here, we examined the patterns of selected ion transporter expression, the mechanisms underlying alterations in glucose metabolism, and pH regulation in human breast cancer cells. Our results show that members of the proton transport family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple negative breast cancer (TNBC), appears to coordinately express monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). Proton efflux, as measured by the glycolytic rate assay, showed pH dependence and a requirement for CA IX expression. Isoform selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests activity is not necessary for this regulation. This supports a mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux.