Tumor invasion and metastasis is mediated by a transition from an epithelial to a mesenchymal phenotype. E-cadherin downregulation in epithelial tumors is associated with tumor progression. In contrast, N-cadherin, normally not expressed in epithelia, is upregulated in breast tumors and is associated with an invasive phenotype. R-cadherin, another classic cadherin known to function in brain, retina, muscle, pancreas, and kidney, has only very recently been linked to epithelial carcinomas. We found that R-cadherin is highly expressed in the breast epithelium and non-transformed mammary cell lines. In breast cancer, R-cadherin is highly expressed in ductal carcinomas in situ but markedly reduced in invasive duct carcinomas especially in advanced tumor areas, suggesting R-cadherin is lost with tumor progression. In support of a tumor suppressive role, knockdown of R-cadherin in normal breast cells disrupted morphogenesis and stimulated invasiveness, whereas overexpression in invasive breast cancer cells induced morphogenesis and inhibited invasion, tumor formation and lung metastasis. Thus, R-cadherin is an overlooked and important epithelial cadherin which exerts a potent suppressive role in breast cancer. In light of the widely appreciated roles that cadherins play in cancer progression, it will be important to elucidate whether R-cadherin is a critical factor and elucidate whether it acts through an adhesive or signaling mechanism.
In Aim 1, we will determine whether R- cad downregulation is associated with malignant progression and evaluate methylation as a mechanism for R- cadherin loss.
In Aim 2, we will map the regions within R-cadherin that determine its suppressive function and differentiate it from the proinvasive N-cadherin. Establishing the clinical relevance of R-cadherin and identifying the segments which mediate suppression could provide leads into signaling pathways and therapeutic strategies to control breast cancer.

Public Health Relevance

We found that R-cadherin is substantially downregulated in breast cancer. We have established a series of in vitro and in vivo models to test tumor suppression by R-cadherin. Interestingly, R-cadherin and N- cadherin are structurally very similar, yet display opposite effects on tumor progression. We have designed a series of studies to study the role of R-cadherin loss in breast cancer progression and map the molecular determinants that mediate its suppressive function as opposed to those that mediate tumor invasion by N- cadherin. We believe these studies have the potential to broaden our understanding of mechanisms that regulate breast cancer progression and have thus the potential to provide insights into therapeutic application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136854-04
Application #
8288276
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Lively, Tracy (LUGO)
Project Start
2009-07-22
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$334,117
Indirect Cost
$132,842
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kim, Seaho; Yao, Jiahong; Suyama, Kimita et al. (2014) Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis. Cancer Res 74:3695-706