Abstract
Overexpression of the human epidermal growth factor receptor-2 (HER2) is associated with aggressive disease in breast and certain other cancers. At a cellular level, the adhesion protein Junctional Adhesion Molecule-A (JAM-A) has been reported to regulate the expression of HER3 via a transcriptional pathway involving FOXA1. Since FOXA1 is also a suggested transcription factor for HER2, this study set out to determine if JAM-A regulates HER2 expression via a similar mechanism. An integrated tripartite approach was taken, involving cellular expression studies after targeted disruption of individual players in the putative pathway, in silico identification of relevant HER2 promoter regions and, finally, interrogation of cancer patient survival databases to deconstruct functionally important links between HER2, JAM-A and FOXA1 gene expression. The outcome of these investigations revealed a unidirectional pathway in which JAM-A expression transcriptionally regulates that of HER2 by influencing the binding of FOXA1 to a specific site in the HER2 gene promoter. Moreover, a correlation between JAM-A and HER2 gene expression was identified in 75% of a sample of 40 cancer types from The Cancer Genome Atlas, and coincident high mean mRNA expression of JAM-A, HER2 and FOXA1 was associated with poorer survival outcomes in HER2-positive (but not HER2-negative) patients with either breast or gastric tumors. These investigations provide the first evidence of a transcriptional pathway linking JAM-A, HER2 and FOXA1 in cancer settings, and support potential future pharmacological targeting of JAM-A as an upstream regulator of HER2.
Highlights
Breast cancers which overexpress the human epidermal growth factor receptor-2(HER2) have been associated with aggressive clinical phenotypes including high grade tumors, increased growth rates, early metastasis, and decreased rates of both disease-free survival and overall survival [1,2]
High Junctional Adhesion Molecule-A (JAM-A) expression is a feature of certain aggressive breast cancers
There are significant positive correlations between JAM-A and HER2 gene expression in multiple other cancers, 30/40 or 75% of The Cancer Genome Atlas (TCGA) subclassifications that can be interrogated on the online platform timer.cistrome.org [29,30]
Summary
Breast cancers which overexpress the human epidermal growth factor receptor-2(HER2) have been associated with aggressive clinical phenotypes including high grade tumors, increased growth rates, early metastasis, and decreased rates of both disease-free survival and overall survival [1,2]. It has been reported that high expression of the adhesion protein Junctional Adhesion Molecule-A (JAM-A) correlates with HER2 expression in breast cancer patient tissues, and that JAM-A regulates HER2 protein stability [3]. This seems at odds with the multiple physiological localizations [4,5] and functions (reviewed by [6]) of JAM-A, including intercellular tight junction assembly, cell polarity, leukocyte transmigration, platelet activation and angiogenesis. In the pathophysiological setting of cancer, JAM-A gene amplification or protein overexpression has recently emerged to positively correlate with aggressive disease and poor patient outcome in multiple carcinomas including breast [3,7,8], glioblastoma, nasopharyngeal, gastric and lung [9–12]. The putative mechanism by which JAM-A regulates HER2 expression involves protection against proteasomal degradation of the latter [3], it is noteworthy that degradation of HER2 can take place either by lysosomal or proteasomal pathways [14]
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