Loss of retinal cadherin facilitates mammary tumor progression and metastasis

Georgia Agiostratidou, Maomi Li, Kimita Suyama, Ines Badano, Rinat Keren, Su Chung, Amy Anzovino, James Hulit, Binzhi Qian, Boumediene Bouzahzah, Eliseo Eugenin, Olivier Loudig, Greg R. Phillips, Joseph Locker, Rachel B. Hazan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The mammary epithelium is thought to be stabilized by cellcell 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. ©2009 American Association for Cancer Research.
    Original languageEnglish
    Pages (from-to)5030-5038
    Number of pages8
    JournalCancer Research
    Volume69
    Issue number12
    DOIs
    Publication statusPublished - 15 Jun 2009

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