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Loss of Retinal Cadherin Facilitates Mammary Tumor Progression and Metastasis

¹ Department of Pathology, Albert Einstein College of Medicine; ² Montefiore Medical Center, Bronx, New York and ³ Department of Neuroscience, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Rachel B. Hazan, Albert Einstein College of Medicine, Department of Pathology, F529S, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: 718-430-3349; Fax: 718-430-8541; E-mail: rhazan{at}aecom.yu.edu.

Key Words: adhesion • adherens junction • invasion • metastasis • signaling

The mammary epithelium is thought to be stabilized by cell-cell adhesion mediated mainly by E-cadherin (E-cad). Here, we show that another cadherin, retinal cadherin (R-cad), is critical for maintenance of the epithelial phenotype. R-cad is expressed in nontransformed mammary epithelium but absent from tumorigenic cell lines. In vivo, R-cad was prominently expressed in the epithelium of both ducts and lobules. In human breast cancer, R-cad was down-regulated with tumor progression, with high expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. By comparison, E-cad expression persisted in invasive breast tumors and cell lines where R-cad was lost. Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression. Conversely, R-cad overexpression in aggressive cell lines induced glandular morphogenesis and inhibited invasiveness, tumor formation, and lung colonization. R-cad also suppressed the matrix metalloproteinase 1 (MMP1), MMP2, and cyclooxygenase 2 gene expression associated with pulmonary metastasis. The data suggest that R-cad is an adhesion molecule of the mammary epithelium, which acts as a critical regulator of the normal phenotype. As a result, R-cad loss contributes to epithelial suppression and metastatic progression. [Cancer Res 2009;69(12):5030–8]