Open AccessADAM 8 expression in invasive breast cancer promotes tumor dissemination and metastasis
Author(s) -
Romagnoli Mathilde,
Mineva Nora D,
Polmear Michael,
Conrad Catharina,
Srinivasan Srimathi,
Loussouarn Delphine,
BarilléNion Sophie,
Georgakoudi Irene,
Dagg Áine,
McDermott Enda W,
Duffy Michael J,
McGowan Patricia M.,
Schlomann Uwe,
Parsons Maddy,
Bartsch Jörg W,
Sonenshein Gail E
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303373
Subject(s) - disintegrin , triple negative breast cancer , cancer research , metastasis , angiogenesis , gene knockdown , breast cancer , medicine , cell culture , biology , cancer , pathology , metalloproteinase , matrix metalloproteinase , genetics
The transmembrane metalloprotease‐disintegrin ADAM 8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM 8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple‐negative breast cancers ( TNBC s). Furthermore, high ADAM 8 levels predicted poor patient outcome. Consistently, ADAM 8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM 8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM 8 stimulated both angiogenesis through release of VEGF ‐A and transendothelial cell migration via β1‐integrin activation. In vivo , treatment with an anti‐ ADAM 8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non‐essential protein under physiological conditions, ADAM 8 represents a promising novel target for treatment of TNBC s, which currently lack targeted therapies and frequently progress with fatal dissemination.