Loss of occludin leads to the progression of human breast cancer

Abstract

Abstract.Occludin is an integral membrane protein localised at tight junctions (TJs). It has become clear that the TJ is an important structure that cancer cells must overcome in order to metastasize successfully. The purpose of this study was to elucidate the importance of the expression of occludin in human breast cancer. Human tissues and breast cancer cell lines were amplified for functional regions of occludin. Tumour tissues showed truncated and/or variant signals. There was also considerable variation in the expression of occludin in the 10 human breast cancer cell lines investigated. Western blotting demonstrated that variants in the MDA-MB-231 and MCF-7 human breast cancer cell lines did not fit the expected occludin signals for changes in phosphorylation status. Immunostaining showed similarly disparate levels of expression. Ribozyme knockdown resulted in increased invasion, reduced adhesion and significantly reduced TJ functions. Q-RT-PCR analysis of 124 tumour and 33 background human breast tissues showed occludin to be significantly decreased in patients with metastatic disease. Immunohistochemical staining showed a decreased expression of occludin in the tumour sections. This study demonstrates for the first time that occludin is differentially expressed in human breast tumour tissues and cell lines. This loss of or aberrant expression has clear repercussions as to the importance of occludin in maintaining TJ integrity in breast tissues. Such inappropriate expression could play a part in breast cancer development.

Occludin: One Protein, Many Forms

“…Interestingly, Occ ⌬E9 localized in the cytoplasm and, unlike wildtype occludin, did not induce mitochondrion-mediated apoptosis or reduce cell invasiveness. As previous publications have demonstrated the antitumorigenic properties of occludin (71,84), these findings have led investigators to speculate on a potential role for the Occ ⌬E9 variant in cancer progression. Again, further investigations will be necessary to confirm such a role.…”

Neutrophil-Epithelial Interactions

“…113 Similarly, altered expression of CAR, occluding, and certain claudins are associated with defective epithelial homeostasis and, in some cases, links to cancer progression. 99,104,114 Inflammation-induced alterations in expression of apical junctional complex proteins are not specific to tight and adherens junctions structures because disruption of intestinal epithelial desmosomal structure during inflammation has also been shown to have potent functional consequences. 115 However, in contrast to the decreased protein expression observed for tight junction molecules, unpublished studies suggest that expression of the desmosomal cadherin desmoglein 2 (Dsg2) may be increased under certain inflammatory conditions.…”

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

“…Some evidence suggests that TJ protein phosphorylation plays an important role in the regulation of cell-cell adhesion [13,14]. It is worth noting that occludin and CRB3, intercellular binding proteins, have been used as epithelial and polarity markers in EMT studies [15,16]. In our study, to understand the complex process of tumor progression, we attempted to demonstrate that estradiol induces EMT-associated mechanisms, including c-Src phosphorylation, p-Src/ZO-1 complex formation, ZO-1/ZONAB nuclear translocation, increased permeability, downregulation of occludin and CRB3 expression, increased N-cadherin expression, and motility of breast cancer cells, through a novel pathway involving TJ proteins.…”