Royal College of Surgeons in Ireland
Smith_2022.pdf (6.93 MB)

Functional antagonism of junctional adhesion molecule-A (JAM-A), overexpressed in breast ductal carcinoma in situ (DCIS), reduces HER2-Positive tumor progression

Download (6.93 MB)
journal contribution
posted on 2022-06-23, 15:11 authored by Yvonne E Smith, Guannan Wang, Ciara L Flynn, Stephen MaddenStephen Madden, Owen MacEneaney, Rodrigo GB Cruz, Cathy E Richards, Hanne Jahns, Marian BrennanMarian Brennan, Mattia Cremona, Bryan HennessyBryan Hennessy, Katherine SheehanKatherine Sheehan, Alexander Casucci, Faizah A Sani, Lance Hudson, Joanna FayJoanna Fay, Sri H Vellanki, Siobhán O'FlahertySiobhán O'Flaherty, Marc DevocelleMarc Devocelle, Arnold HillArnold Hill, Kieran Brennan, Saraswati Sukumar, Ann HopkinsAnn Hopkins
Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS.


Health Research Board of Ireland, grant HRA/POR/2014/545

Komen Foundation via the Susan Love Research Foundation (DSLRF)

Royal College of Surgeons in Ireland

Science Foundation Ireland (grant 13/IA/1994,16/RI/3737)

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

Breast Cancer Ireland



The original article is available at

Published Citation

Smith YE. et al. Functional antagonism of junctional adhesion molecule-A (JAM-A), overexpressed in breast ductal carcinoma in situ (DCIS), reduces HER2-Positive tumor progression. Cancers (Basel). 2022;14(5):1303

Publication Date

3 March 2022

PubMed ID



  • Beaumont Hospital
  • Chemistry
  • Data Science Centre
  • Pathology
  • School of Pharmacy and Biomolecular Sciences
  • Surgery
  • School of Medicine
  • Undergraduate Research

Research Area

  • Cancer
  • Surgical Science and Practice
  • Chemistry and Pharmaceutical Sciences




  • Published Version (Version of Record)