Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal

Abstract

Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion channels in cancer is now well established, the role of inositol (1,4,5)-trisphosphate (IP₃) receptors (IP₃Rs) remains enigmatic. If the three IP₃Rs subtypes expression have been identified in various cancers, little is known about their physiological role. Here, we investigated the involvement of IP₃R type 3 (IP₃R₃) in the migration processes of three human breast cancer cell lines showing different migration velocities: the low-migrating MCF-7 and the highly migrating and invasive MDA-MB-231 and MDA-MB-435S cell lines. We show that a higher IP₃R3 expression level, but not IP₃R1 nor IP₃R2, is correlated to a stronger cell line migration capacity and a sustained calcium signal. Interestingly, silencing of IP₃R3 highlights an oscillating calcium signaling profile and leads to a significant decrease of cell migration capacities of the three breast cancer cell lines. Conversely, stable overexpression of IP₃R3 in MCF-7 cells significantly increases their migration capacities. This effect is completely reversed by IP₃R3 silencing. In conclusion, we demonstrate that IP₃R3 expression level increases the migration capacity of human breast cancer cells by changing the calcium signature.