BioProject

Membrane association of the tumor suppressor, annexin A6 (AnxA6), has been shown to regulate plasma membrane permeability to extracellular Ca2+, inhibit anchorage-independent tumor cell growth and paradoxically, promote tumor cell motility by mechanisms that remains poorly understood. More...

Membrane association of the tumor suppressor, annexin A6 (AnxA6), has been shown to regulate plasma membrane permeability to extracellular Ca2+, inhibit anchorage-independent tumor cell growth and paradoxically, promote tumor cell motility by mechanisms that remains poorly understood. Here, we identified RasGRF2, a Ca2+-activated Ras-specific guanine nucleotide exchange factor, as a major effector of AnxA6-elicited tumor-associated phenotypes in breast cancer cells. We demonstrate that reduced expression or loss of AnxA6 in breast cancer cells is associated with up-regulation of RasGRF2, increased Ras activity and consequently, early onset and rapid growth of xenograft tumors. Meanwhile, up-regulation of AnxA6 in AnxA6-low breast cancer cells is associated with a decrease in Ras activity and growth of xenograft tumors but on the contrary, an increase in Cdc42 activity and EGF-stimulated cell motility. Inhibition of Ca2+ influx into AnxA6-low breast cancer cells via Ni2+-sensitive or non-selective Ca2+ channels dose-dependently suppressed the expression of RasGRF2, induced the expression of AnxA6 and consequently, inhibited tumor cell proliferation. Finally, aberrant expression of RasGRF2 may be triggered by AnxA6-mediated or pharmacological inhibition of non-selective Ca2+ channels and occurs at least in part, by promoter methylation. These data for the first time identify RasGRF2 as a major effector of AnxA6-dependent breast tumor growth and motility and that regulated Ca2+ influx and/or RasGRF2 may be potential therapeutic targets for rapidly growing AnxA6-low breast carcinomas Overall design: Four replicates of cell lines generated by stable transfection of control and two distinct shRNAs targeting annexin A6 in the mesencymal-like BT-549 breast cancer cell line Less...