A novel functional polymorphism in the transforming growth factor-beta2 gene promoter and tumor progression in breast cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-08, Vol.66 (15), p.7554-7561
• Main Authors: Beisner, Julia, Buck, Miriam B, Fritz, Peter, Dippon, Jürgen, Schwab, Matthias, Brauch, Hiltrud, Zugmaier, Gerhard, Pfizenmaier, Klaus, Knabbe, Cornelius
• Format: Article
• Language: English
• Subjects: Alleles; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Disease Progression; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Binding; Sp1 Transcription Factor - metabolism; Transcriptional Activation; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta2
• ISSN: 0008-5472

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.