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: Masato Murakami, Costanza Giampietro, Monica Giannotta, Monica Corada, Ilaria Torselli, Fabrizio Orsenigo, Andrea Cocito, Giovanni d'Ario, Giovanni Mazzarol, Stefano Confalonieri, Pier Paolo Di Fiore, Elisabetta Dejana
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e21242 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21695058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Polyomavirus Transforming
• Cell Adhesion Molecules
• F11r protein, mouse
• Receptors, Cell Surface

Topics

• Animals
• Antigens, Polyomavirus Transforming (genetics)
• Apoptosis (genetics)
• Breast Neoplasms (diagnosis, genetics, pathology, virology)
• Cell Adhesion Molecules (deficiency, genetics)
• Cell Line, Tumor
• Disease Progression
• Female
• Gene Deletion
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Intercellular Junctions (metabolism)
• Intracellular Space (metabolism)
• Mammary Tumor Virus, Mouse (genetics)
• Mice
• Middle Aged
• Prognosis
• Promoter Regions, Genetic (genetics)
• Receptors, Cell Surface (deficiency, genetics)