| First Author | Yin YJ | Year | 2006 |
| Journal | Cancer Res | Volume | 66 |
| Issue | 10 | Pages | 5224-33 |
| PubMed ID | 16707447 | Mgi Jnum | J:109058 |
| Mgi Id | MGI:3625655 | Doi | 10.1158/0008-5472.CAN-05-4234 |
| Citation | Yin YJ, et al. (2006) Mammary gland tissue targeted overexpression of human protease-activated receptor 1 reveals a novel link to beta-catenin stabilization. Cancer Res 66(10):5224-33 |
| abstractText | Protease-activated receptor 1 (PAR1) is emerging with distinct assignments in tumor biology. We show that tissue targeted overexpression of hPar1 in mice mammary glands results in precocious hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. These glands exhibit increased levels of wnt-4 and wnt-7b and a striking beta-catenin stabilization. Nuclear localization of beta-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PAR1 induces beta-catenin nuclear localization also in established epithelial tumor cell lines of intact beta-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PAR1-mediated beta-catenin stabilization is taking place primarily via the increase of Wnt expression. Enforced expression of a specific Wnt antagonist family member, secreted frizzled receptor protein 5 (SFRP5), efficiently inhibited PAR1-induced beta-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced beta-catenin nuclear accumulation. This takes place most likely via inhibition of Wnt signaling at the level of cell surface (forming a neutralizing complex of 'Receptors-SFRP-Wnt'). Furthermore, depletion of hPar1 by small interfering RNA (siRNA) vectors markedly inhibited PAR1-induced Wnt-4. The striking stabilization of beta-catenin, inhibited by SFRPs on one hand and Wnt-4 silencing by hPar1 siRNA on the other hand, points to a novel role of hPar1 in Wnt-mediated beta-catenin stabilization. This link between PAR1 and beta-catenin may bear substantial implications both in developmental and tumor progression processes. |
