Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2

Abstract

As the majority of patients with basal-like breast carcinoma present with invasive, metastatic disease that do not respond to available therapies, it is essential to identify new therapeutic targets that impact invasion and metastasis. Protease-activated receptor 1 (PAR1), a G-protein coupled receptor has been shown to act as an oncogene, but underlying mechanisms are not well understood. Here, we show that ectopic expression of functionally active PAR1 in MCF-7 cells induced a hormone-refractory, invasive phenotype representative of advanced basal-like breast carcinoma that readily formed metastatic lesions in lungs of mice. PAR1 was found to globally upregulate mesenchymal markers, including vimentin, a direct target of PAR1, and downregulate the epithelial markers including E-cadherin, as well as estrogen receptor. In contrast, non-signaling PAR1 mutant receptor did not lead to an invasive, hormone refractory phenotype. PAR1 expression increased spheroid formation and the level of stemness markers and self-renewal capacity in human breast cancer cells. We identified HMGA2 (high mobility group A2) as an important regulator of PAR1-mediated invasion. Inhibition of PAR1 signaling suppresses HMGA2-driven invasion in breast cancer cells. HMGA2 gene and protein are highly expressed in metastatic breast cancer cells. Overall, our results show that PAR1/HMGA2 pathway may present a novel therapeutic target.