Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion.
Local disruption of the integrity of both the myoepithelial cell layer and the basement membrane is an indispensable prerequisite for the initiation of invasion and the conversion of human breast ductal carcinoma in situ (DCIS) to infiltrating ductal carcinoma (IDC). We previously reported that human endometase/matrilysin-2/matrix metalloproteinase (MMP) 26-mediated pro-gelatinase B (MMP-9) activation promoted invasion of human prostate carcinoma cells by dissolving basement membrane proteins (Y. G. Zhao et al., J. Biol. Chem., 278: 15056-15064, 2003). Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K(i) values of 1.6 and 0.62 nM, respectively. TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro. The expression levels of MMP-26, MMP-9, TIMP-2, and TIMP-4 proteins in DCIS were significantly higher than those in IDC, atypical intraductal hyperplasia, and normal breast epithelia adjacent to DCIS and IDC by immunohistochemistry and integrated morphometry analysis. Double immunofluorescence labeling and confocal laser scanning microscopy revealed that MMP-26 was colocalized with MMP-9, TIMP-2, and TIMP-4 in DCIS cells. Higher levels of MMP-26 mRNA were also detected in DCIS cells by in situ hybridization.
Zhao
Yun-Ge
YG
Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
Xiao
Ai-Zhen
AZ
Park
Hyun I
HI
Newcomer
Robert G
RG
Yan
Mei
M
Man
Yan-Gao
YG
Heffelfinger
Sue C
SC
Sang
Qing-Xiang Amy
QX
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D044584:Carcinoma, Ductal / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053505:Matrix Metalloproteinases, Secreted; D009361:Neoplasm Invasiveness; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C410599:MMP26 protein, human