Immunohistochemical demonstration of the zinc metalloprotease insulin-degrading enzyme in normal and malignant human breast: correlation with tissue insulin levels.
Insulin is a hormone crucial to metabolism and an essential growth factor for normal and neoplastic tissues. We have now determined insulin in extracts of 23 primary breast cancer specimens and of non-neoplastic breast tissues by a chemiluminescent immunoassay. Remarkably, insulin was measured only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland were each insulin-negative. We also performed immunohistochemistry for insulin-degrading enzyme (IDE), a cytoplasmic zinc metalloprotease belonging to the inverzincin family and participating in insulin cleavage. IDE was detected in most insulin-positive grade 3 carcinomas, indicating that it might be dysfunctional in these anaplastic tumors. IDE was equally present in the insulin-negative grade 2 carcinomas. Moreover, five grade 3 carcinomas and one grade 2 carcinoma displayed a loss of heterozygosity in the 10q chromosomal region harboring the IDE gene, but, despite these alterations, IDE was detected immunohistochemically, indicating a retention of the second allele. Compared to the expression of IDE in 92% of the tumors examined, only 57% of 21 normal breast specimens stained positively for IDE. In contrast to this increase in IDE-positive epithelial cells in breast cancer vs. normal breast, additional immunohistochemical analysis of 17 node-positive breast carcinomas and corresponding tumor-bearing lymph nodes showed that IDE expression decreases from primary tumor to lymph node metastasis. Altogether, this study represents the first demonstration of IDE in normal and neoplastic human mammary tissues. Our present report should also provide an experimental starting point towards exploring a potential role of IDE in the control of tumor progression.
Radulescu
Razvan T
RT
Clinical Research Unit, Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 München, Germany. razvan.radulescu@lrz.tum.de
Hufnagel
Carla
C
Luppa
Peter
P
Hellebrand
Heide
H
Kuo
Wen-Liang
WL
Rosner
Marsha Rich
MR
Harbeck
Nadia
N
Giersig
Cecylia
C
Meindl
Alfons
A
Schmitt
Manfred
M
Weirich
Gregor
G
D000328:Adult; D000368:Aged; D001940:Breast / Q000201:enzymology*; D001943:Breast Neoplasms / Q000201:enzymology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007339:Insulysin / Q000378:metabolism*; D008593:Menopause; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012016:Reference Values
D007328:Insulin; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D007339:Insulysin