Lack of effective translational regulation of PLD expression and exosome biogenesis in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is difficult to treat since cells lack the three receptors (ES, PR, or HER) that the most effective treatments target. We have used a well-established TNBC cell line (MDA-MB-231) from which we found evidence in support for a phospholipase D (PLD)-mediated tumor growth and metastasis: high levels of expression of PLD, as well as the absence of inhibitory miRs (such as miR-203) and 3'-mRNA PARN deadenylase activity in these cells. Such findings are not present in a luminal B cell line, MCF-7, and we propose a new miR•PARN•PLD node that is not uniform across breast cancer molecular subtypes and as such TNBC could be pharmacologically targeted differentially. We review the participation of PLD and phosphatidic acid (PA), its enzymatic product, as new "players" in breast cancer biology, with the aspects of regulation of the tumor microenvironment, macrophage polarization, regulation of PLD transcripts by specific miRs and deadenylases, and PLD-regulated exosome biogenesis. A new signaling miR•PARN•PLD node could serve as new biomarkers for TNBC abnormal signaling and metastatic disease staging, potentially before metastases are able to be visualized using conventional imaging.