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A transcriptional link between HER2, JAM-A and FOXA1 in breast cancer

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posted on 23.06.2022, 14:48 by Rodrigo Bernardo Cruz, Stephen MaddenStephen Madden, Kieran Brennan, Ann HopkinsAnn Hopkins
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.

Funding

CAPES, Coordination for the Improvement of Higher Education Personnel—Brazil (Science without Borders Programme-Process 013306/2013-08)

Science Foundation Ireland (grants 2008/RFP/NSC1427 and 08/RFP/ NSC1427 TIDA Feasibility 10)

Health Research Board of Ireland (HRA-POR-2014-545)

Breast Cancer Ireland and Science Foundation Ireland (13/IA/1994)

History

Associated research data files

The following publicly available datasets were interrogated during this study: http://timer.cistrome.org/ https://kmplot.com/analysis/index.php?p=service&cancer=breast https://www.encodeproject.org/ https://genexplain.com/transfac/ http://genome.ucsc.edu/ (accessed on 15 December 2021)

Comments

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

Published Citation

Cruz RGB, Madden SF, Brennan K, Hopkins AM. A transcriptional link between HER2, JAM-A and FOXA1 in breast cancer. Cells. 2022;11(4):735

Publication Date

19 February 2022

PubMed ID

35203384

Department/Unit

  • Beaumont Hospital
  • Data Science Centre
  • Surgery

Research Area

  • Cancer

Publisher

MDPI AG

Version

  • Published Version (Version of Record)