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

3^rd World Congress on Women’s Health & Breast Cancer

October 03-05, 2016 London, UK

Lidija Covic

Tufts Medical Center, USA

Posters & Accepted Abstracts: J Cancer Sci Ther

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. Proteaseactivated 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 hormonerefractory, 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 down-regulate the epithelial markers including E-cadherin, as well as estrogen receptor. In contrast, non-signaling PAR1 mutant receptor did not lead to invasive phenotype. PAR1 expression increased spheroid formation and the level of stemness markers and self-renewal capacity in human breast cancer cells. Here, we identified HMGA2 (high mobility group A2) as 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.

Biography :

Email: lcovic@tuftsmedicalcenter.org