Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1

Simple Summary Signaling from the human epidermal growth factor receptor (HER) family of proteins increases in many cancers, including breast. HER2-high breast cancers are successfully treated with anti-HER2 therapies, but these drugs are limited by the fact that patients frequently develop resistance to them. One common mechanism by which resistance develops is when tumors acquire high levels of a family member called HER3. We had previously shown that a protein called JAM-A regulates the level of HER2 in breast cancer cells, and is associated with the development of resistance to HER2-targeted therapies. In this study we show for the first time that JAM-A levels also regulate those of HER3. Using breast cancer cell and tissue models and culminating in patient tissue material, we provide evidence that JAM-A regulates HER3 expression via a pathway involving the transcription factors beta-catenin and FOXA1. We suggest that JAM-A merits future investigation as a novel drug target for its potential to reduce HER3 tumorigenic signaling and to offset the development of resistance to HER2-targeted therapies. The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving beta-catenin. Our data suggest a novel model whereby JAM-A expression regulates beta-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.