Increasing evidence supports a cancer stem cell (CSC) model in which CSCs are the subpopulation of tumour cells that drive tumor initiation, drug resistance and relapse/recurrence. Current chemoprevention and chemotherapies are not efficacious in the treatment of advanced and metastatic disease, at least in part due to the resistance of CSC, so novel approaches are required to specifically target CSC populations.
Sphingolipid, specifically, sphingosine-1-phosphate (S1P)-related signaling has been linked to ability of CSCs to direct their immune microenvironment, grow and survive. However, in breast CSCs the sphingolipid receptor expression levels, role and mechanisms of signaling remains poorly understood.
We assessed the level of S1P receptors expression in MCF-7 parental breast adenocarcinoma cell line and mammospheres of breast cancer stem cells (BCSCs) grown in the presence or absence of cytokines. PCR analysis demonstrated that expression level of S1PR3 in mammosphere-enriched BCSCs was nearly 4-times higher than in the parental cell line grown in monolayer. Notably, cytokine treatment effectively decreased not only the size and growth rate of mammospheres, but also the levels of S1PR3 in mammospheres. These findings were confirmed using confocal microscopy. Fluorescent staining of S1PR3 indicated plasma membrane and cytoplasmic localization of this receptor in BCSCs. Cytokine treatment induced significant decline in the level of S1PR3 expression. These data show for the first time that certain S1P receptors (e.g. S1PR3) are elevated in BCSC and might be implicated in cytokine-regulated growth responses. We expect that a better understanding of S1P signaling in breast CSC will inform new approaches to target this population of cells.