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Mammary Gland Tissue Targeted Overexpression of Human Protease-Activated Receptor 1 Reveals a Novel Link to ß-Catenin Stabilization

¹ Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel and ² Department of Public Health, Sapporo Medical University S1, Chuo-ku, Sapporo, Japan

Requests for reprints: Rachel Bar-Shavit, Department of Oncology, Hadassah-Hebrew University Hospital, P.O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2-677-7563; Fax: 972-2-642-2794; E-mail: barshav{at}md.huji.ac.il.

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 ß-catenin stabilization. Nuclear localization of ß-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PAR1 induces ß-catenin nuclear localization also in established epithelial tumor cell lines of intact ß-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PAR1-mediated ß-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 ß-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced ß-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 ß-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 ß-catenin stabilization. This link between PAR1 and ß-catenin may bear substantial implications both in developmental and tumor progression processes. (Cancer Res 2006; 66(10): 5224-32)

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