High frequency of loss of allelic integrity at Wilms' tumor suppressor gene-1 locus in advanced breast tumors associated with aggressiveness of the tumor.
BACKGROUND
The product of Wilms' tumor suppressor gene (WT1), a nuclear transcription factor, regulates the expression of the insulin-like growth factor (IGF) and transforming growth factor (TGF) systems, both of which are implicated in breast tumorigenesis and are known to facilitate angiogenesis. In the present study, WT1 allelic integrity was examined by Loss of Heterozygosity (LOH) studies in infiltrating breast carcinoma (n=60), ductal carcinoma in situ (DCIS) (n=10) and benign breast disease (n=5) patients, to determine its possible association with tumor progression.


METHODS
LOH at the WT1 locus (11p13) as determined by PCR-RFLP for Hinf1 restriction site and was subsequently examined for its association with intratumoral expression of various growth factors i.e. TGF-beta1, IGF-II, IGF-1R and angiogenesis (VEGF and Intratumoral micro-vessel density) in breast carcinoma.


RESULTS
Six of 22 (27.2%) genetically heterozygous of infiltrating breast carcinoma and 1 of 4 DCIS cases showed loss of one allele at WT1 locus. Histologically, the tumors with LOH at WT1 were Intraductal carcinoma (IDC) and were of grade II and III. There was no correlation in the appearance of LOH at WT1 locus with age, tumor stage, menopausal status, chemotherapy status and lymph node metastasis. The expression of factor IGF-II and its receptor, IGF-1R was significantly higher in carcinoma having LOH at WT1 locus. A positive correlation was observed between the TGF-beta1, VEGF expression and IMD scores in infiltrating carcinoma.


CONCLUSIONS
The current study indicates that the high frequency of loss of allelic integrity at Wilms' tumor suppressor gene-1 locus in high-graded breast tumors is associated with aggressiveness of the tumor.
Gupta
S
S
Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
Joshi
K
K
Wig
J D
JD
Arora
S K
SK
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology*; D016162:Genes, Wilms Tumor; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis; D019656:Loss of Heterozygosity; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1