Loss of retinal cadherin facilitates mammary tumor progression and metastasis.
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.
Agiostratidou
Georgia
G
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Li
Maomi
M
Suyama
Kimita
K
Badano
Ines
I
Keren
Rinat
R
Chung
Su
S
Anzovino
Amy
A
Hulit
James
J
Qian
Binzhi
B
Bouzahzah
Boumediene
B
Eugenin
Eliseo
E
Loudig
Olivier
O
Phillips
Greg R
GR
Locker
Joseph
J
Hazan
Rachel B
RB
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*
D015820:Cadherins; D017931:DNA Primers; C083970:R-cadherin; D034741:RNA, Small Interfering