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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

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posted on 2023-01-09, 17:13 authored by Rodrigo GB Cruz, Stephen MaddenStephen Madden, Cathy E Richards, Sri Harikrishna Vellanki, Hanne Jahns, Lance Hudson, Joanna FayJoanna Fay, Naoimh O'Farrell, Katherine SheehanKatherine Sheehan, Karin Jirström, Kieran Brennan, Ann HopkinsAnn Hopkins
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 β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-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.

Funding

Understanding the mechanistic role and druggability of JAM-A, an emerging upstream regulator of breast cancer tumourigenic signalling, using in vitro and in vivo methodologies and a novel small molecu | Funder: Science Foundation Ireland (SFI) | Grant ID: 13/IA/1994

Uncovering a novel regulation of receptor tyrosine kinase signalling by junctional adhesion molecule-A (JAM-A) in breast cancer | Funder: Science Without Borders | Grant ID: CAPES - 13306-13-8, 2008/RFP/NSC1427

Breast Cancer Ireland

Science Foundation Ireland 2008/RFP/NSC1427

History

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Cruz RGB. et al. 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. Cancers (Basel). 2021;13(4):871.

Publication Date

19 February 2021

PubMed ID

33669586

Department/Unit

  • Beaumont Hospital
  • Data Science Centre
  • Pathology
  • Surgery

Research Area

  • Cancer
  • Neurological and Psychiatric Disorders
  • Gynaecology, Obstetrics and Perinatal Health

Publisher

MDPI

Version

  • Published Version (Version of Record)