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.
Highlights
JAM-A (Junctional adhesion molecule-A) is a small immunoglobulin expressed by different cell types including epithelial, endothelial cells, leukocytes, dendridic cells and platelets [1,2,3,4]
JAM-A was expressed in the normal epithelium of mammary duct and glands in wild type mice and expression was maintained in mammary tumor virus promoter (MMTV)-Polyoma virus middle T (PyVmT) mammary tumor cells and in metastatic tumor cells in the lymph nodes and lung (Figure S1)
The results presented here show that JAM-A is a negative prognostic factor for murine and human mammary tumor growth
Summary
JAM-A (Junctional adhesion molecule-A) is a small immunoglobulin expressed by different cell types including epithelial, endothelial cells, leukocytes, dendridic cells and platelets [1,2,3,4]. Rip1Tag mice develop pancreatic tissue hyperplasia and highly vascularized adenoma which progress to invasive carcinoma [9]. In this particular model, tumor cells do not express JAM-A which is present in the cells of the stroma. Naik MU et al [10] reported that JAM-A expression reduces breast cancer cell lines’ invasion and motility in vitro and is inversely related to carcinoma aggressiveness and metastatic behavior in human patients. McSherry et al [11] using a larger clinical data set showed that JAM-A expression is a negative prognostic factor in breast cancer
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