title: Roles for E-cadherin cell surface regulation in cancer.
abstract: The loss of E-cadherin expression in association with the epithelial-mesenchymal transition (EMT) occurs frequently during tumor metastasis. However, metastases often retain E-cadherin expression, an EMT is not required for metastasis, and metastases can arise from clusters of tumor cells. We demonstrate that the regulation of the adhesive activity of E-cadherin present at the cell surface by an inside-out signaling mechanism is important in cancer. First, we find that the metastasis of an E-cadherin-expressing mammary cell line from the mammary gland to the lung depends on reduced E-cadherin adhesive function. An activating monoclonal antibody to E-cadherin that induces a high adhesive state significantly reduced the number of cells metastasized to the lung without affecting the growth in size of the primary tumor in the mammary gland. Second, we find that many cancer-associated germline missense mutations in the E-cadherin gene in patients with hereditary diffuse gastric cancer selectively affect the mechanism of inside-out cell surface regulation without inhibiting basic E-cadherin adhesion function. This suggests that genetic deficits in E-cadherin cell surface regulation contribute to cancer progression. Analysis of these mutations also provides insights into the molecular mechanisms underlying cadherin regulation at the cell surface.
authors: Department of Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, VA 22908.
authors: Yuliya I
authors: YI
authors: Petrova
authors: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101.
authors: Leslayann
authors: L
authors: Schecterson
authors: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101 gumbiner@uw.edu.|Departments of Pediatrics and Biochemistry, University of Washington School of Medicine, Seattle, WA 98195.
authors: Barry M
authors: BM
authors: Gumbiner
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015820:Cadherins; D011956:Receptors, Cell Surface; D014157:Transcription Factors