DDAH1 and DDAH2 drive vasculogenic mimicry and more aggressive phenotypes in triple negative breast cancer cells.

The overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) and 2 (DDAH2) has been associated with several types of cancer. Specifically, DDAH1 has been shown to play a critical role in the establishment of a vascular network by tumour cells, vasculogenic mimicry (VM), in triple negative breast cancer (TNBC). In turn, VM favours TNBC progression and is associated with poor patient prognosis. DDAH1 is well characterised in its capacity to metabolise asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. By contrast, DDAH2 is incapable of metabolising ADMA, and its ADMA-independent functions and role in TNBC are unknown. In an in vitro MDA-MB-231 TNBC cell model, CRISPR-Cas9 knockout and siRNA knockdown of either DDAH1 or DDAH2 significantly reduced VM. This effect was accompanied by a significant reduction in proliferation, migration, invasion, and Vascular endothelial growth factor A (VEGF-A) secretion. These results suggest ADMA-independent mechanisms for DDAH2 in the occurrence of VM and identify DDAH2 as a novel therapeutic target in TNBC.