Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous 
physiological processes and represent targets for therapeutics for a vast array 
of diseases, their role in tumor biology is under appreciated. 
Protease-activated receptors (PARs) form a family which belongs to GPCR class A. 
PAR1&2 emerge with a central role in epithelial malignancies. Although the part 
of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly 
understood. We review hereby past, present, and future cancer-associated PAR 
biology. Mainly, their role in physiological (placenta-cytotophobalst) and 
patho-physiological invasion processes. The identification and characterization 
of signal pleckstrin homology (PH)-domain-binding motifs established critical 
sites for breast cancer growth in PAR1&2. Among the proteins found to harbor 
important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx 
and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein 
association and is sufficient to markedly reduce PAR2-instigated breast tumor 
growth in vivo as also placental extravillous trophoblast (EVT) invasion in 
vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable 
to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these 
motifs with physiological significance and underscoring the importance of these 
previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological 
and physiological invasion processes.