Gap junctions in normal and neoplastic mammary gland

Abstract

Progress in the characterization of gap junctions and their constituent connexin sub-units is leading to a greater understanding of the structure, function, and regulation of this cell-cell communication channel. Although much of the experimental evidence generated to date is correlative, recent work utilizing reverse genetic approaches to manipulate connexin gene function has provided direct evidence that intercellular communication via gap junctions plays key roles in development, cellular differentiation, and organogenesis. Pathogenic mutations in human connexin genes have now been identified. Furthermore, a considerable body of experimental evidence correlates a loss of junctional communication with progression to a malignant phenotype. Although the cell biology of the mammary gland has been extensively studied, the role(s) of gap junctions in the development, differentiation, and maintenance of this tissue are unknown. Gap junctions were first reported in the mammary gland following freeze-fracture and electron microscopic analyses. The development of anti-connexin antibodies and the cloning of individual connexin isoforms have enabled this work to be extended, but there are contradictory reports in the temporal expression patterns of these proteins within mammary epithelium. In addition, a recent report in this Journal has implied by immunocytochemistry that there is up-regulation of connexin protein in some human breast tumours, a novel observation which may be inconsistent with the proposed tumour suppressor role for gap junctions.