title: Interplay between neural-cadherin and vascular endothelial-cadherin in breast cancer progression.
abstract: BACKGROUND
  Deregulation of cadherin expression, in particular the loss of epithelial (E)-cadherin and gain of neural (N)-cadherin, has been implicated in carcinoma progression. We previously showed that endothelial cell-specific vascular endothelial (VE)-cadherin can be expressed aberrantly on tumor cells both in human breast cancer and in experimental mouse mammary carcinoma. Functional analyses revealed that VE-cadherin promotes tumor cell proliferation and invasion by stimulating transforming growth factor (TGF)-β signaling. Here, we investigate the functional interplay between N-cadherin and VE-cadherin in breast cancer.
  
  
  METHODS
  The expression of N-cadherin and VE-cadherin was evaluated by immunohistochemistry in a tissue microarray with 84 invasive human breast carcinomas. VE-cadherin and N-cadherin expression in mouse mammary carcinoma cells was manipulated by RNA interference or overexpression, and cells were then analyzed by immunofluorescence, reverse transcriptase-polymerase chain reaction, and western blot. Experimental tumors were generated by transplantation of the modified mouse mammary carcinoma cells into immunocompetent mice. Tumor growth was monitored, and tumor tissue was subjected to histological analysis.
  
  
  RESULTS
  VE-cadherin and N-cadherin were largely co-expressed in invasive human breast cancers. Silencing of N-cadherin in mouse mammary carcinoma cells led to decreased VE-cadherin expression and induced changes indicative of mesenchymal-epithelial transition, as indicated by re-induction of E-cadherin, localization of β-catenin at the cell membrane, decreased expression of vimentin and SIP1, and gain of epithelial morphology. Suppression of N-cadherin expression also inhibited tumor growth in vivo, even when VE-cadherin expression was forced.
  
  
  CONCLUSIONS
  Our results highlight the critical role of N-cadherin in breast cancer progression and show that N-cadherin is involved in maintaining the malignant tumor cell phenotype. The presence of N-cadherin prevents the re-expression of E-cadherin and localization of β-catenin at the plasma membrane of mesenchymal mammary carcinoma cells. N-cadherin is also required to maintain the expression of VE-cadherin in malignant tumor cells but not vice versa. Thus, N-cadherin acts in concert with VE-cadherin to promote tumor growth.
authors.forename: Maryam
authors.initials: M
authors.lastname: Rezaei
authors.forename: Katrin
authors.initials: K
authors.lastname: Friedrich
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Kuzmanov
authors.forename: Antje
authors.initials: A
authors.lastname: Kettelhake
authors.forename: Myriam
authors.initials: M
authors.lastname: Labelle
authors.forename: Hans
authors.initials: H
authors.lastname: Schnittler
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baretton
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D014746:Vimentin / Q000096:biosynthesis; D051176:beta Catenin / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014746:Vimentin; D051176:beta Catenin; D000099152:Cadherin 5; C108381:GEMIN2 protein, human