Adenocarcinoma, Adenocarcinoma, Mucinous, Adult, Aged, Aged, 80 and over, Antigens, CD29, Blotting, Western, Breast Neoplasms, Carcinoma, Medullary, Cell Adhesion, Cell Adhesion Molecules, Cell Movement, Cell Proliferation, Female, Fluorescent Antibody Technique, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunoenzyme Techniques, Immunoglobulins, Middle Aged, Neoplasm Invasiveness, Oligonucleotide Array Sequence Analysis, Prognosis, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tissue Array Analysis, Tumor Markers, Biological, Wound Healing
The cell-cell adhesion protein junctional adhesion molecule-A (JAM-A) influences epithelial cell morphology and migration. As migration is required for tumor cell invasion and metastasis, we sought to elucidate the role of JAM-A in invasive breast cancer. A breast cancer tissue microarray was analyzed for JAM-A protein expression, in parallel with analysis of JAM-A gene expression data from a breast cancer clinical dataset. Our data demonstrate a novel association between JAM-A gene and protein upregulation and poor prognosis in breast cancer. To mechanistically dissect this process, we used lentiviral technology to stably knock down JAM-A gene expression by shRNA in MCF7 breast cancer cells, which express high-endogenous levels of JAM-A. We also antagonized JAM-A function in wild-type MCF7 cells using an inhibitory antibody that blocks JAM-A dimerization. Knockdown or functional antagonism of JAM-A decreased breast cancer cell migration in scratch-wound assays. Reductions in beta1-integrin protein levels were observed after JAM-A-knockdown in MCF7 cells, suggesting a mechanism for reduced motility after loss of JAM-A. Consistent with this hypothesis, tissue microarray analysis of beta1-integrin protein expression in invasive breast cancer tissues revealed a trend toward high beta1-integrin protein levels being indicative of poor prognosis. Twenty-two percent of patients were observed to coexpress high levels of JAM-A and beta1-integrin protein, and MDA-MB-231 breast cells stably overexpressing JAM-A showed an increase in beta1-integrin protein expression. Our results are consistent with a previously unreported role for JAM-A overexpression as a possible mechanism contributing to progression in primary breast cancer; and a potential therapeutic target.
McSherry EA, McGee SF, Jirstrom K, Doyle EM, Brennan DJ, Landberg G, Dervan PA, Hopkins AM, Gallagher WM. JAM-A Expression Positively Correlates with Poor Prognosis in Breast Cancer Patients. International Journal of Cancer. 2009 Sept 15;125(6):1343-51.