title: CD151 regulates tumorigenesis by modulating the communication between tumor cells and endothelium.
abstract: The tetraspanin CD151 forms stoichiometric complexes with laminin-binding integrins (e.g., alpha3beta1, alpha6beta1, and alpha6beta4) and regulates their ligand-binding and signaling functions. We have found that high expression of CD151 in breast cancers is associated with decreased overall survival (3.44-fold higher risk of death). Five-year estimated survival rates were 45.8% (95% confidence interval, 16.4-71.4%) for CD151-positive patients and 79.9% (95% confidence interval, 62.2-90.0%) for CD151-negative patients. Furthermore, CD151 was positively associated with axillary lymph node involvement. To study the biological significance of this observation, we investigated the contribution of CD151 in breast cancer tumorigenesis using MDA-MB-231 cells as a model system. Stable down-regulation of this tetraspanin by short-hairpin RNA decreased the tumorigenicity of these cells in mice. Detailed immunohistologic analysis of CD151(+) and CD151(-) xenografts showed differences in tumor vascular pattern. Vascularization observed at the subcutaneous border of the CD151(+) tumors was less pronounced or absent in the CD151(-) xenografts. In vitro experiments have established that depletion of CD151 did not affect the inherent proliferative capacity of breast cancer cells in three-dimensional extracellular matrices, but modified their responses to endothelial cells in coculture experiments. The modulatory activity of CD151 was dependent on its association with both alpha3beta1 and alpha6beta4 integrins. These data point to a new role of CD151 in tumorigenesis, whereby it functions as an important regulator of communication between tumor cells and endothelial cells. These results also identify CD151 as a potentially novel prognostic marker and target for therapy in breast cancer.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, The University of Birmingham, Edgbaston, United Kingdom.
authors.forename: Rafal
authors.initials: R
authors.lastname: Sadej
authors.forename: Hanna
authors.initials: H
authors.lastname: Romanska
authors.forename: Gouri
authors.initials: G
authors.lastname: Baldwin
authors.forename: Katerina
authors.initials: K
authors.lastname: Gkirtzimanaki
authors.forename: Vera
authors.initials: V
authors.lastname: Novitskaya
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Filer
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Krcova
authors.forename: Renata
authors.initials: R
authors.lastname: Kusinska
authors.forename: Jiri
authors.initials: J
authors.lastname: Ehrmann
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Radzislaw
authors.initials: R
authors.lastname: Kordek
authors.forename: Piotr
authors.initials: P
authors.lastname: Potemski
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: El-Nasir
authors.initials: el-N
authors.lastname: Lalani
authors.forename: Fedor
authors.initials: F
authors.lastname: Berditchevski
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D060185:Tetraspanin 24; D046509:Tissue Culture Techniques
chemical_list: D015703:Antigens, CD; C554715:CD151 protein, human; C554716:Cd151 protein, mouse; D004338:Drug Combinations; D016023:Integrins; D007797:Laminin; D011509:Proteoglycans; D060185:Tetraspanin 24; C059485:matrigel; D003094:Collagen