Junctional adhesion molecule-A is co-expressed with HER2 in breast tumors and acts as a novel regulator of HER2 protein degradation and signaling.

Junctional adhesion molecule-A (JAM-A) is a membranous cell-cell adhesion protein involved in tight-junction formation in epithelial and endothelial cells. Its overexpression in breast tumors has recently been linked with increased risk of metastasis. We sought to identify if JAM-A overexpression was associated with specific subtypes of breast cancer as defined by the expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor. To this end, JAM-A immunohistochemistry was performed in two breast cancer tissue microarrays. In parallel, cross-talk between JAM-A, HER2 and ER was examined in several breast cell lines, using complementary genetic and pharmacological approaches. High JAM-A expression correlated significantly with HER2 protein expression, ER negativity, lower patient age, high-grade breast cancers, and aggressive luminal B, HER2 and basal subtypes of breast cancer. JAM-A and HER2 were co-expressed at high levels in vitro in SKBR3, UACC-812, UACC-893 and MCF7-HER2 cells. Knockdown or functional antagonism of HER2 did not alter JAM-A expression in any cell line tested. Interestingly, however, JAM-A knockdown decreased HER2 and ER-α expression, resulting in reduced levels of phospho-(active) AKT without an effect on the extracellular signal-related kinase phosphorylation. The downstream effects of JAM-A knockdown on HER2 and phospho-AKT were partially reversed upon treatment with the proteasomal inhibitor MG132. We conclude that JAM-A is co-expressed with HER2 and associates with aggressive breast cancer phenotypes. Furthermore, we speculate that JAM-A may regulate HER2 proteasomal degradation and activity, potentially offering a promise as a therapeutic target in HER2-positive breast cancers.

Molecular basis of invasion in breast cancer.

Cancer cell invasion involves the breaching of tissue barriers by cancer cells, and the subsequent infiltration of these cells throughout the surrounding tissue. In breast cancer, invasion at the molecular level requires the coordinated efforts of numerous processes within the cancer cell and its surroundings. Accumulation of genetic changes which impair the regulation of cell growth and death is generally accepted to initiate cancer. Loss of cell-adhesion molecules, resulting in a loss in tissue architecture, in parallel with matrix remodelling may also confer a motile or migratory advantage to breast cancer cells. The tumour microenvironment may further influence the behaviour of these cancer cells through expression of cytokines, growth factors, and proteases promoting chemotaxis and invasion. This review will attempt to summarise recent work on these fundamental processes influencing or facilitating breast cancer cell invasion. (Part of a Multi-author Review).