Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression.

Autor: Smith YE; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Wang G; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Flynn CL; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Madden SF; Data Science Centre, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland., MacEneaney O; Department of Pathology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Cruz RGB; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Richards CE; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Jahns H; School of Veterinary Medicine, University College Dublin, Dublin 4, Ireland., Brennan M; School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland., Cremona M; Department of Medical Oncology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Hennessy BT; Department of Medical Oncology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Sheehan K; Department of Pathology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Casucci A; School of Medicine, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland., Sani FA; School of Medicine, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland., Hudson L; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Fay J; Department of Pathology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Vellanki SH; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., O'Flaherty S; Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland., Devocelle M; Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland., Hill ADK; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Brennan K; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland., Sukumar S; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Hopkins AM; Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Mar 03; Vol. 14 (5). Date of Electronic Publication: 2022 Mar 03.
DOI: 10.3390/cancers14051303
Abstrakt: 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.
Databáze: MEDLINE
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