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.
%0 Journal Article
%1 beisner2006novel
%A Beisner, Julia
%A Buck, Miriam B.
%A Fritz, Peter
%A Dippon, Jürgen
%A Schwab, Matthias
%A Brauch, Hiltrud
%A Zugmaier, Gerhard
%A Pfizenmaier, Klaus
%A Knabbe, Cornelius
%D 2006
%J Cancer Research
%K 2006 izi pfizenmaier
%N 15
%P 7554--7561
%R 10.1158/0008-5472.CAN-06-0634
%T A Novel Functional Polymorphism in the Transforming Growth Factor-β2 Gene Promoter and Tumor Progression in Breast Cancer
%U http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-06-0634
%V 66
%X 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.
%@ 0008-5472 (Print)$\backslash$r0008-5472 (Linking)
@article{beisner2006novel,
abstract = {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.},
added-at = {2018-02-01T17:01:43.000+0100},
author = {Beisner, Julia and Buck, Miriam B. and Fritz, Peter and Dippon, J{\"{u}}rgen and Schwab, Matthias and Brauch, Hiltrud and Zugmaier, Gerhard and Pfizenmaier, Klaus and Knabbe, Cornelius},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/236fc6f016737d4cbe98571a3122124cb/cristiano},
doi = {10.1158/0008-5472.CAN-06-0634},
interhash = {cc8e345d3acc0a1d27e5f036f98c07e1},
intrahash = {36fc6f016737d4cbe98571a3122124cb},
isbn = {0008-5472 (Print)$\backslash$r0008-5472 (Linking)},
issn = {0008-5472},
journal = {Cancer Research},
keywords = {2006 izi pfizenmaier},
month = aug,
number = 15,
pages = {7554--7561},
timestamp = {2019-01-17T14:02:12.000+0100},
title = {A Novel Functional Polymorphism in the Transforming Growth Factor-β2 Gene Promoter and Tumor Progression in Breast Cancer},
url = {http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-06-0634},
volume = 66,
year = 2006
}