Expression of extracellular matrix metalloproteases inducer on micrometastatic and primary mammary carcinoma cells.
OBJECTIVE
EMMPRIN (extracellular matrix metalloprotease inducer) is a glycosylated member of the immunoglobulin superfamily known to stimulate the production of matrix metalloproteases (MMPs) 1, 2, and 3 and MT1-MMP in peritumoral fibroblasts. We here evaluated whether EMMPRIN expression is related to tumor progression in human breast cancer.


METHODS
An immunohistochemical study using high-density tissue microarrays (n = 2222 breast cancer samples) and EMMPRIN-specific antibodies HIM6 and MEM-M6/1 was performed, and staining results were statistically correlated with various clinicopathological parameters. To analyze the putative association between EMMPRIN expression and bone marrow (BM) micrometastasis, an additional set of 55 breast tumors from patients with or without micrometastatic cells as determined with anti-cytokeratin antibody A45-B/B3 were included in our study. Cytokeratin-positive cells in BM were costained with EMMPRIN-specific antibody 1G6.2.


RESULTS
Positive EMMPRIN staining correlated significantly with various histopathological risk factors (higher tumor grade, increased tumor size, negative estrogen receptor status and progesterone receptor status, and higher mitotic index) as well as decreased tumor-specific survival (log-rank, P = 0.0027). In particular, in patients > 50 years (i.e., postmenopausal women), EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (relative risk = 1.7, 95% confidence interval 1.4-4.3, P = 0.036). An involvement of EMMPRIN in tumor progression was also supported by the fact that it was expressed on approximately 90% of micrometastatic cells in BM.


CONCLUSIONS
EMMPRIN expression in primary tumor predicts an unfavorable prognosis in breast cancer, suggesting a crucial role of EMMPRIN in progression of human mammary carcinomas.
Reimers
Natalie
N
Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Zafrakas
Kristine
K
Assmann
Volker
V
Egen
Cornelia
C
Riethdorf
Lutz
L
Riethdorf
Sabine
S
Berger
Jürgen
J
Ebel
Sebastian
S
Jänicke
Fritz
F
Sauter
Guido
G
Pantel
Klaus
K
D015703:Antigens, CD / Q000096:biosynthesis* / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000502:physiology*; D051926:Basigin; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005109:Extracellular Matrix / Q000201:enzymology* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011980:Receptors, Progesterone / Q000378:metabolism; D012306:Risk; D012307:Risk Factors; D013997:Time Factors
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497886:BSG protein, human; D011980:Receptors, Progesterone; D051926:Basigin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases