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. 2006 Apr;8(4):319-29.
doi: 10.1593/neo.05682.

ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease

Rainer Kuefer  1 , Kathleen C Day, Celina G Kleer, Michael S Sabel, Matthias D Hofer, Sooryanarayana Varambally, Christoph S Zorn, Arul M Chinnaiyan, Mark A Rubin, Mark L Day
Affiliations

ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease

Rainer Kuefer et al. Neoplasia. 2006 Apr.

Abstract

The aim of the current study was to evaluate the expression of ADAM15 disintegrin (ADAM15) in a broad spectrum of human tumors. The transcript for ADAM15 was found to be highly upregulated in a variety of tumor cDNA expression arrays. ADAM15 protein expression was examined in tissue microarrays (TMAs) consisting of 638 tissue cores. TMA analysis revealed that ADAM15 protein was significantly increased in multiple types of adenocarcinoma, specifically in prostate and breast cancer specimens. Statistical association was observed with disease progression within clinical parameters of predictive outcome for both prostate and breast cancers, pertaining to Gleason sum and angioinvasion, respectively. In this report, we also present data from a cDNA microarray of prostate cancer (PCa), where we compared transfected LNCaP cells that overexpress ADAM15 to vector control cells. In these experiments, we found that ADAM15 expression was associated with the induction of specific proteases and protease inhibitors, particularly tissue inhibitor of metalloproteinase 2, as validated in a separate PCa TMA. These results suggest that ADAM15 is generally overexpressed in adenocarcinoma and is highly associated with metastatic progression of prostate and breast cancers.

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Figures

Figure 1
Figure 1
(A) Comparison of benign tissue samples with neoplastic tissue samples of a multitumor TMA independent of organ site. There is a highly significant difference (Mann-Whitney U test, P < .001) in the expression values of ADAM15 between normal and neoplastic tissue samples, with an overexpression of ADAM15 in neoplastic tissue. (B) Comparison of non-adenocarcinomas and adenocarcinomas of different origins. There is a highly significant difference in the protein expression of ADAM 15 within these two categories. In adenocarcinomas, ADAM15 is significantly higher compared to other types of neoplastic tissue (P < .001).
Figure 2
Figure 2
(A) ADAM15 is significantly overexpressed at the RNA level in neoplastic prostate tissue. Its expression is significantly higher in localized PCa than in benign prostatic tissue, and expression is highest in patients in the hormone-refractory metastatic group. (B) Three hundred twenty-one tissue samples were evaluated in this TMA. Staining intensity was significantly stronger in metastatic tissue samples than in localized PCa. Normal prostate tissue showed very low levels of ADAM15 expression (P < .001). (C) There is a strong association between ADAM15 expression in the TMA and Gleason sum categorized as <7 and ≥7 (P = .014).
Figure 3
Figure 3
(A) Protein expression of ADAM15 in different subtypes of breast cancer from breast TMA. A significantly higher expression of ADAM15 was seen in neoplastic samples (P < .001). Within different categories of malignant subtypes, the differences are not significant. The highest levels of ADAM15 were present in metastatic breast cancer tissue samples. Examples of two tissue cores (one from a normal tissue and the other from an invasive breast carcinoma) are depicted. (B) Breast cancer with angioinvasion has a significantly higher expression of ADAM15 protein than tissues without angioinvasion (P = .006).
Figure 4
Figure 4
(A) Over-expression of ADAM15 protein in LNCaP cells in culture where, LNCaP M142 cells are shown under bright field microscopy and (B) the same field of cells under fluorescence, (magnification for both is 20X). Note that ADAM15/GFP fusion protein is localized to the cell membranes and the cell/cell junctions.
Figure 5
Figure 5
Protein expression of TIMP2 in prostate tissues. TIMP2 expression is significantly higher in PCa compared to normal or benign prostate tissue (Mann-Whitney U test, P < .001).
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