@article{6c0c19ea7be24d9fadba43d05a1f8b49,
title = "Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression",
abstract = "Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAMA) 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.",
keywords = "DCIS, antagonism, breast cancer, in vivo, intra-ductal, junctional adhesion molecule-A (JAM-A), tight junction",
author = "Smith, {Yvonne E.} and Guannan Wang and Flynn, {Ciara L.} and Madden, {Stephen F.} and Owen Maceneaney and Cruz, {Rodrigo G.B.} and Richards, {Cathy E.} and Hanne Jahns and Marian Brennan and Mattia Cremona and Hennessy, {Bryan T.} and Katherine Sheehan and Alexander Casucci and Sani, {Faizah A.} and Lance Hudson and Joanna Fay and Vellanki, {Sri H.} and Siobhan O{\textquoteright}flaherty and Marc Devocelle and Hill, {Arnold D.K.} and Kieran Brennan and Saraswati Sukumar and Hopkins, {Ann M.}",
note = "Funding Information: Funding: This research was principally funded by the Health Research Board of Ireland, grant HRA/POR/2014/545 (to AMH). The i.duc study was part-funded by a pilot grant to SS and AMH from the Komen Foundation via the Susan Love Research Foundation (DSLRF), and seed funding from RCSI. CER, SHV, and MD received funding from Science Foundation Ireland (grant 13/IA/1994 to AMH, grant 16/RI/3737 to MD). RGBC received funding from CAPES, Coordination for the Improvement of Higher Education Personnel—Brazil (Science without Borders Programme—Process 013306/2013-08). AMH also thanks Breast Cancer Ireland for supplementary funding. Funding Information: This research was principally funded by the Health Research Board of Ireland, grant HRA/POR/2014/545 (to AMH). The i.duc study was part-funded by a pilot grant to SS and AMH from the Komen Foundation via the Susan Love Research Foundation (DSLRF), and seed funding from RCSI. CER, SHV, and MD received funding from Science Foundation Ireland (grant 13/IA/1994 to AMH, grant 16/RI/3737 to MD). RGBC received funding from CAPES, Coordination for the Improvement of Higher Education Personnel—Brazil (Science without Borders Programme—Process 013306/2013-08). AMH also thanks Breast Cancer Ireland for supplementary funding. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2022",
month = mar,
day = "1",
doi = "10.3390/cancers14051303",
language = "English (US)",
volume = "14",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "5",
}