Loss of the tight junction MAGUK ZO-1 in breast cancer - Relationship to glandular differentiation and loss of heterozygosity

Membrane-associated guanylate kinase homologs (MAGUKs) may play a role in c ellular functions preventing tumorigenesis as indicated by the neoplastic p henotype caused by genetic loss of the MAGUK Dig in Drosophila. To test thi s possibility, we examined the expression and subcellular localization of t he tight junction MAGUK ZO-1, as well as the cell adhesion molecule E-cadhe rin, in paraffin-embedded breast cancer samples, using immunohistochemistry and confocal microscopy, As expected, normal tissue showed intense stainin g for ZO-1 at the position of the epithelial tight junctions, but this stai ning was reduced or lost in 69% of breast cancers analyzed (II = 48). In in filtrating ductal carcinomas (n = 38) there was a reduction in staining in 42% of well differentiated, in 83% of moderately differentiated and 93% of poorly differentiated tumors. ZO-1 staining was positively correlated with tumor differentiation (P =.011) and more specifically with the glandular di fferentiation of tumors (P =.0019). Reduction in ZO-1 staining was strongly correlated with reduced E-cadherin staining (P = 4.9 x 10(-5)). The result s suggest that down-regulation of ZO-1 expression and its failure to accumu late at cell junctions may be causally related to cancer progression. To de tect loss of heterozygosity, the ZO-1 gene tjp-1 was mapped relative to oth er markers in 15q13 and polymorphic markers flanking tjp-1 were identified. The marker D15S1019 showed loss of heterozygosity in 23% of informative tu mors (II = 13), Loss of a tjp-1-linked marker suggests that genetic loss ma y, in some cases, be responsible for the reduction in ZO-1 expression in br east cancer.