Inorganic Phosphate (Pi) in the Breast Cancer Microenvironment: Production, Transport and Signal Transduction as Potential Targets for Anticancer Strategies

Abstract

Tumor cells develop a high demand for inorganic phosphate (Pi) due to their high growth rates and energy requirements. Serum Pi concentrations in cancer patients have been found to be two to four times higher than baseline levels in healthy individuals. Twofold Pi accumulation was observed in breast cancer cells in the mouse tumor microenvironment. In the breast tumoral microenvironment, ectonucleotidases and ectophosphatases-presenting catalytic sites facing the extracellular environment-could be involved in the extracellular release of Pi to be internalized by Pi transporters to fuel the high energy requirement typical of cancer cells. Two Pi transporters were characterized in breast cancer cells (Na+-dependent and H+-dependent) with strong associations with tumor processes such as proliferation, migration, adhesion, and epithelium-mesenchymal transition (EMT). Moreover, a high extracellular Pi concentration stimulates ROS production in triple-negative breast cancer cells by Pi transport stimulation. Several compounds show a potent ability to inhibit ectonucleotidases, ectophosphatases, Pi transporters, and Pi-modulated signal pathways in breast cancer cells and regulate proliferation, migration, adhesion, and EMT. This review article aimed to gather the relevant experimental records regarding Pi's effects on the breast cancer microenvironment and points to possible inhibitors for ectonucleotidases, ectophosphatases, Pi transporters, and Pi-modulated signal pathways as potential chemotherapeutic agents or Pi acting as a potent enhancer of classical chemical-induced cytotoxicity in triple-negative breast cancer cells.

Keywords: H+-dependent Pi transport; Inorganic phosphate; Na+-dependent Pi transport; breast cancer microenvironment; ectonucleotidases; ectophosphatases.