One of the tight junction components, zonula occludens protein 2 (ZO-2), is expressed as two isoforms, ZO-2A and ZO-2C, in normal epithelia. In pancreatic adenocarcinoma of the ductal type ZO-2A is absent, but none of the common mechanisms of gene inactivation is responsible for lack of ZO-2A expression. In the current study, we report the complete organization of the human zo-2 gene (tjp-2), its alternative splicing, and its expression in normal and neoplastic tissues of several organ sites. In addition to pancreatic adenocarcinoma, ZO-2 was found to be de-regulated in breast adenocarcinoma, but not in colon or prostate adenocarcinoma. The latter are considered to be of acinar rather than ductal type. Thus, our data indicate the importance of zo-2 (tjp-2) gene regulation in ductal cancer development and should help to understand the defects of intercellular interactions, critical for suppressing the malignant phenotype.