Inorganic phosphate as a novel signalling molecule with antiproliferative action in MDA-MB-231 breast cancer cells

Inorganic phosphate (Pi) is an essential nutrient to living organisms. It plays a key role in diverse physiological functions, including osteoblast differentiation and skeletal mineralization. Relevantly, Pi is emerging as an important signalling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. To our knowledge, no research has been directed at determining the consequences of elevated Pi on behaviour of breast cancer cells. In this study we investigate the effects of Pi on proliferation of MDA-MB-231 breast cancer cells. Here we report that Pi inhibits proliferation of MDA-MB-231 cells by slowing-down cell cycle progression, without apoptosis occurrence. We found that Pi causes the cells to accumulate in G1 phase in a dose and time dependent manner. Accordingly, G1 accumulation was associated with a decrease of cyclin A and cyclin E and an increase of cell cycle inhibitors p21 and p27 protein levels, respectively. Moreover, the Pi-induced antiproliferative effect was dinamically accompanied by profound changes in ERK1/2 and STAT3 protein and phosphorylation levels in response to Pi. Altogether, our data represent the first evidence of Pi acting as a novel signalling molecule in MDA-MB-231 breast cancer cells, capable of eliciting a strong antiproliferative action. The potential clinical significance and therapeutic applications by our data will be discussed.