Connexin 43 loss induces early signs of neoplasia in normal mammary epithelium -

Abstract

Being one of the very few organs that continue to develop and differentiate late during the lifespan of an individual, the mammary gland is a good model to study how changes in the interaction between cells and their environment, as well as modulations in tissue architecture, might lead to tumor development. The differentiation of the mammary epithelium encompasses the attachment of epithelial cells to the basement membrane (a specialized form of extracellular matrix), thus creating the basal pole and the formation of the lumen apically by sealing cell-cell contacts with tight junctions, which overall defines the basoapical polarity axis. Perturbations in mammary epithelial cell adhesion, communication and polarity could bring about one of the most common types of cancers in women worldwide, breast cancer. Normal differentiation at the tissue level requires establishment of a specific architecture, which is partly accomplished through cell junctions and polarity. The hallmark of breast cancer is the disruption of cellular communication between mammary epithelial cells. As such, it is essential to understand the stepwise mechanism by which cellular architecture and communication is lost prior to cancer initiation. Our laboratory has long been interested in understanding the role of connexin 43 (Cx43) as a major gap junction (GJ) protein that mediates optimal cell-cell communication and differentiation events in the mammary gland. Cx43 has been previously reported to be exclusively localized to myoepithelial cells in the mammary gland, however, we presented immunohistochemical evidence showing the localization of Cx43 at the apical membrane of luminal epithelial cells of normal breast tissue structures (acini). In order to understand the role of Cx43 in breast epithelial differentiation, a three-dimensional cell culture system that promotes the differentiation of HMT-3522 S1 (S1) non-tumorigenic breast epithelial cells was used. Our results suggested that Cx43 is the only Cx expressed in S1 cells and was abundant