Progesterone as a cause of Breast cancer

Protease Activated Receptors and Progesterone

Focal Adhesion Kinase (FAK) is a protein that belongs to the family of cytoplasmic tyrosine kinases. When activated, FAK associates with FA (focal adhesion) proteins allowing autophosphorylation at the docking site of the cells. Mature FA complexes, together with phosphorylated FAK recruit other proteins to allow cell detachment The protease-activated receptors (PARs) are a family of four vascular recep­tors that respond to local changes in the proteolytic environment. These receptors are activated by thrombin. PARs are important in tissue repair and response to inju­ries In tumor cells, PAR2 is activated by factor Vlla-tissue factor (TF), regulat­ing proangiogenic growth factor expression. TF is strongly induced by progesterone in breast cancer cell lines

The ability of progestins to regulate PAR expression appears to be cell spe­cific (endometrium, cervix, vascular vessels, breast etc.). This action is also progestin’s specific; levonorgestrel down regulates PARI in the endometrium, MPA up regulates PAR 1 expresion in vascular endothelial cells etc. .Over expression of PARI is a feature of many metastatic cancers. These cancers are more invasive in vitro, It has been demonstrated that progesterone regulates PARI at the mRNA and protein levels This regulation is dependent on the presence of PR. Advanced breast cancer is associated with a hypercoagulable state. Progesterone has been shown to enhance the coagulation cascade proteins TF and PARI promoting cancer cells angiogenesis, coagulation, migration and invasion. This may be another mechanism by which progesterone may contrib­ute to the increase in breast cancer incidence in women using continuous com­bined HRT.