A novel functional polymorphism in the transforming growth factor-beta2 gene promoter and tumor progression in breast cancer.
Transforming growth factor-beta (TGF-beta), a multifunctional growth factor, plays an important role in breast cancer. There is increasing evidence that enhanced expression of TGF-beta promotes breast cancer progression contributing to metastasis and invasiveness of the tumor. We identified a functional polymorphism in the TGFB2 promoter, a 4-bp insertion at position -246 relative to the transcriptional start site (-246ins). Transient transfection experiments showed that the -246ins polymorphism significantly increased TGFB2 promoter activity in breast cancer cells. Electrophoretic mobility shift assays revealed binding of the transcription factor Sp1 to the -246ins allele. Overexpression of Sp1 enhanced promoter activity of the -246ins allele, demonstrating that Sp1 mediates transcriptional activation. Furthermore, the -246ins allele was associated with enhanced TGF-beta(2) expression in breast cancer tissue (P = 0.0005). To evaluate the role of the polymorphism in breast cancer, frequency of the -246ins allele was determined in breast cancer patients (n = 78) and healthy female controls (n = 143). No significant differences were found. However, the presence of the -246ins allele was associated with lymph node metastasis (P = 0.003). The -246ins allele was a significant predictor for lymph node metastasis independent of estrogen and progesterone receptor status in a multivariate logistic regression analysis (P = 0.0118, odds ratio, 5.18; 95% confidence interval, 1.44-18.62). We provide evidence that the TGFB2 -246ins polymorphism leads to enhanced TGF-beta(2) expression levels in vivo and might thereby contribute to tumor progression and development of metastases.
Beisner
Julia
J
Department of Clinical Chemistry, Robert-Bosch-Hospital, Auerbachstrasse 110, 70376 Stuttgart, Germany.
Buck
Miriam B
MB
Fritz
Peter
P
Dippon
Jürgen
J
Schwab
Matthias
M
Brauch
Hiltrud
H
Zugmaier
Gerhard
G
Pfizenmaier
Klaus
K
Knabbe
Cornelius
C
D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D053781:Transforming Growth Factor beta2
D016329:Sp1 Transcription Factor; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2