title: Loss of retinal cadherin facilitates mammary tumor progression and metastasis.
abstract: 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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Agiostratidou
authors.forename: Maomi
authors.initials: M
authors.lastname: Li
authors.forename: Kimita
authors.initials: K
authors.lastname: Suyama
authors.forename: Ines
authors.initials: I
authors.lastname: Badano
authors.forename: Rinat
authors.initials: R
authors.lastname: Keren
authors.forename: Su
authors.initials: S
authors.lastname: Chung
authors.forename: Amy
authors.initials: A
authors.lastname: Anzovino
authors.forename: James
authors.initials: J
authors.lastname: Hulit
authors.forename: Binzhi
authors.initials: B
authors.lastname: Qian
authors.forename: Boumediene
authors.initials: B
authors.lastname: Bouzahzah
authors.forename: Eliseo
authors.initials: E
authors.lastname: Eugenin
authors.forename: Olivier
authors.initials: O
authors.lastname: Loudig
authors.forename: Greg R
authors.initials: GR
authors.lastname: Phillips
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Hazan
mesh_terms: D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D012160:Retina / Q000378:metabolism*
chemical_list: D015820:Cadherins; D017931:DNA Primers; C083970:R-cadherin; D034741:RNA, Small Interfering