JAM-A expression positively correlates with poor prognosis in breast cancer patients.
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
Elaine A
EA
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
McGee
Sharon F
SF
Jirstrom
Karin
K
Doyle
Emma M
EM
Brennan
Donal J
DJ
Landberg
Goran
G
Dervan
Peter A
PA
Hopkins
Ann M
AM
Gallagher
William M
WM
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis; D014945:Wound Healing
D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C407243:F11R protein, human; D007136:Immunoglobulins; D019012:Integrin beta1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface