Expression of ADAM‐9 mRNA and protein in human breast cancer

Abstract

The ADAMs (a disintegrin and metalloprotease) are membrane proteins containing both protease and adhesion domains and thus may be potentially important in cancer invasion and metastasis. The aim of our study was to investigate the distribution and potential clinical significance of ADAM-9 in breast cancer. ADAM-9 expression was measured using both reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. ADAM-9 mRNA was expressed more frequently in both breast carcinomas (72/110, 66%) and fibroadenomas (21/38, 55%) compared to normal breast tissue (6/25, 24%) (p ‫؍‬ 0.0004, p ‫؍‬ 0.028, respectively). Multiple forms of ADAM-9 protein were detected by Western blotting, i.e., at 124, 84 and 48 kDa under reducing conditions and at 115, 76, 55, 52 and 46 kDa under nonreducing conditions. The 84 and 55 kDa forms were detected more frequently in the primary cancers compared to normal breast tissue (p < 0.0001, p ‫؍‬ 0.0002, respectively). In addition, relative levels of the 84 kDa mature form were significantly higher in the primary cancers than in the fibroadenomas (p ‫؍‬ 0.003), while the reverse was found for the 124 kDa precursor form (p ‫؍‬ 0.026). In the carcinomas, the 84 kDa form of ADAM-9 protein was expressed at higher levels in node-positive than node-negative cancers (p ‫؍‬ 0.05) and correlated positively with HER-2/neu protein levels (r ‫؍‬ 0.313, p ‫؍‬ 0.016). This is the first report to describe expression of any ADAM in a large number of human carcinomas. © 2003 Wiley-Liss, Inc. Key words: breast cancer; ADAMs; ADAM-9, HER-2/neu; metastasisThe process of cancer invasion and metastasis is a multistep event that involves angiogenesis, local invasion, cell migration, intravasation, extravasation and growth at a secondary site (for review, see reference 1). Although multiple genes have been implicated in cancer dissemination, among the best characterised are those encoding matrix degrading proteases and adhesion proteins (for review, see reference 2). Proteases such as urokinase plasminogen activator (uPA) and specific matrix metalloproteinases (MMPs) degrade or remodel the extracellular matrix (ECM) allowing cancer cells to invade locally and ultimately form distant metastases. 3 Proteases may also promote metastasis by releasing or activating factors [e.g., fibroblast growth factor-2 (FGF-2), transforming growth factor-␤ (TGF-␤), vascular endothelial growth factor (VEGF)], which enhance cell growth, cell migration and angiogenesis. 4,5 Consistent with their role in metastasis, high levels of multiple proteases have been associated with adverse prognosis in different malignancies (for review, see reference 6).As with proteases, adhesion molecules are also involved at multiple stages during invasion and metastasis. 2,7 In the initial stages of the metastatic pathway, cells must detach themselves from their neighbouring cells and adhere to the basement membrane. As the invading cell migrates through the extracellular matrix (ECM), the leading edge undergoes consecutive cycles of adhesio...

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…For example, active ADAM-28 which is overexpressed in breast carcinoma cells contributes to the regulation of cell proliferation through IGFBP-3 cleavage, enhancing the bioavailability of IGF-I [146]. Alternative splicing could also be an important tool used by cancer cells to acquire an invasive phenotype since, for example, different isoforms of ADAM-9 proteins and ADAM-15 mRNA have been detected in breast cancer cells [74,147]. This last finding could give the opportunity to set up a powerful diagnostic tool by studying the differential production of ADAM-9 or -15 domains.…”

“…Some ADAMs could be relevant markers of therapeutic response. ADAM-9 and ADAM-11 mRNA levels in tumours are indeed associated with better response to tamoxifen therapy and ADAM-9 protein production is an indicator of poor prognosis [147,148]. Patients displaying elevated levels of ADAMTS-8 and low levels of ADAMTS-15 have a general poor clinical outcome [149].…”

A Secreted Form of ADAM9 Promotes Carcinoma Invasion through Tumor-Stromal Interactions

“…Despite these observations, the role of ADAM9 in cancer progression has not been explored. However, it was recently reported that in breast carcinoma increased expression of ADAM9 correlates with cancer progression (22) and elevated mRNA levels of both ADAM9 and ADAM12 have been found in liver metastases from colon carcinomas (23). Moreover, overexpression of ADAM9 in nonsmall cell lung cancer correlates with metastasis to the brain (24).…”

ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation

“…Any of these activities can be involved in tumorigenesis (Seals and Courtneidge, 2003). Owing to their multiple functions, some members of the ADAM family have been suspected of involvement in the pathogenesis of breast cancer (O'Shea et al, 2003), prostate cancer (McCulloch et al, 2004), non-small-cell lung cancer (Shintani et al, 2004), and glioblastoma (Kodama et al, 2004), as well as gastric cancer (GC) (Carl-McGrath et al, 2005). However, the association between ADAM proteins and gastric carcinogenesis remains unclear.…”