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

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Basal-like breast carcinoma often presents as metastatic disease unresponsive to therapy.
• Protease-activated receptor 1 (PAR1) is implicated as an oncogene, but its role in invasion and metastasis is unclear.

Purpose of the Study:

• To investigate the role of Protease-activated receptor 1 (PAR1) in driving the invasive and metastatic phenotype of basal-like breast carcinoma.
• To identify molecular mechanisms underlying PAR1-mediated invasion and metastasis.

Main Methods:

• Ectopic expression of functional PAR1 in MCF-7 breast cancer cells.
• Analysis of epithelial-mesenchymal transition (EMT) markers (vimentin, E-cadherin) and estrogen receptor status.
• Assessment of spheroid formation, stemness markers, and self-renewal capacity.
• Investigation of the role of High Mobility Group A2 (HMGA2) in PAR1-mediated invasion.

Main Results:

• PAR1 expression induced a hormone-refractory, invasive phenotype and lung metastasis in mice.
• PAR1 upregulated mesenchymal markers (e.g., vimentin) and downregulated epithelial markers (e.g., E-cadherin) and estrogen receptor.
• PAR1 increased spheroid formation, stemness, and self-renewal capacity.
• HMGA2 was identified as a key regulator of PAR1-driven invasion, with high expression in metastatic cells.

Conclusions:

• The PAR1/HMGA2 signaling pathway is a critical driver of invasion and metastasis in basal-like breast carcinoma.
• PAR1 promotes an aggressive, hormone-refractory, and stem-like phenotype.
• Targeting the PAR1/HMGA2 pathway represents a promising therapeutic strategy for advanced breast cancer.