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.

N-cadherin regulates mammary tumor cell migration through Akt3 suppression

“…To further validate that the effects of N-cadherin on Akt3 expression were not because of confounding effects from other cadherins present in mammary epithelial cells such as R-cadherin, 16 we transfected N-cad-Myc into mouse L cells that are fibroblasts devoid of endogenous cadherins. In these cells, N-cad was also found to downregulate Akt3 expression without affecting Akt1 or Akt2 levels compared with control vector-transfected L cells (Figure 3e).…”

Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models

“…Expression of cadherins in MTC is poorly documented (28) and sunitinib treatment induced up-and downregulation of CDH4 or R-cadherin and CDH6, respectively. R-cadherin acts as a critical regulator of the normal phenotype and its loss contributes to epithelial suppression and metastatic progression (34). Aberrant expression of cadherin-6 is associated with a poor prognosis.…”

Signaling mechanism of cell adhesion molecules in breast cancer metastasis: potential therapeutic targets

“…In breast cancer, R-cadherin was high-level expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. R-cad suppressed tumor formation and lung colonization in vivo and was associated with repression of the MMP1, MMP2, cyclooxygenase 2 (Cox2) gene signature characteristic of pulmonary metastasis [42]. Johnson et al showed that inappropriate expression of R-cadherin in BT-20 breast tumor cells results in decreased expression of endogenous caherins including E-, P-cdherin (cadherin switch), and induced cell motility via Rho GTPase activation [43].…”