R-Cadherin in Breast Cancer Suppression

Summary

Principal Investigator: Rachel B Hazan
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2009-07-22 - 2014-05-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Leukocyte Biomarkers for Predicting Human Breast Cancer Outcomes
    LAURA J VAN 'T VEER; Fiscal Year: 2013
    ..of outcomes in human breast cancer with leukocyte transcriptomes and novel leukocyte biomarkers;and Project 3 will drive translation of leukocyte biomarkers into clinically applicable diagnostic and therapeutic probes ..
  2. Functional Imaging of Twist induced breast cancer
    Venu Raman; Fiscal Year: 2013
    ..In the long term, these studies will help in the pathological diagnosis of breast cancer and provide insights that will contribute to the development of novel imaging markers and chemotherapeutic drugs for breast cancer. ..
  3. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  4. Muc4 Involvement in Mammary Tumor Progression
    Kermit L Carraway; Fiscal Year: 2013
    ..Overall, these studies will validate Muc4 as a novel contributor to breast cancer progression, and will begin to unravel biochemical pathways that might ultimately be exploited for therapeutic intervention. ..
  5. Syndecan-1 in Stromal Fibroblasts of Breast Carcinomas
    Andreas Friedl; Fiscal Year: 2013
    ..The knowledge generated with this work may lead to novel therapies that target the structure of this scaffold and prevent the escape of cancer cells. ..
  6. Mechanisms of Deregulation of Matriptase in Breast Cancer
    Chen Yong Lin; Fiscal Year: 2013
    ....
  7. MT-MMP/DDR cross talk at the tumor cell-matrix interface and cancer progression
    RAFAEL A FRIDMAN; Fiscal Year: 2013
    ..We hope that this new knowledge will help to develop better therapeutic and diagnostic strategies to improve survival in breast cancer patients. ..
  8. INTEGRATIVE PATHOPHYSIOLOGY OF SOLID TUMORS
    Rakesh K Jain; Fiscal Year: 2013
    ..abstract_text> ..
  9. KLF4 regulation of epithelial/mesenchymal transition in breast cancer
    Ruth A Keri; Fiscal Year: 2013
    ..Together, these studies will reveal the molecular circuitry controlled by KLF4 that modulates the epithelial phenotype and has significant implications for specifying metastatic potential. ..
  10. Regulation of Snail1 in cancer metastasis
    Callie Ann Sprunger Corsa; Fiscal Year: 2013
    ..This research will unravel novel molecular mechanisms regulating EMT in cancer that contribute to invasion and metastasis, and will help to develop better therapies for treating breast cancer patients in the future. ..