title: Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression.
abstract: Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A null mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A null mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target.
authors.affiliation: IFOM, Foundation FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.forename: Monica
authors.initials: M
authors.lastname: Giannotta
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Ilaria
authors.initials: I
authors.lastname: Torselli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.forename: Andrea
authors.initials: A
authors.lastname: Cocito
authors.forename: Giovanni
authors.initials: G
authors.lastname: d'Ario
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface