A Novel Functional Polymorphism in the Transforming Growth Factor-{szligbeta} sub(2) 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, Juergen, Schwab, Matthias, Brauch, Hiltrud, Zugmaier, Gerhard, Pfizenmaier, Klaus, Knabbe, Cornelius
• Format: Article
• Language: English
• ISSN: 0008-5472

Transforming growth factor-{szligbeta} (TGF-{szligbeta}), a multifunctional growth factor, plays an important role in breast cancer. There is increasing evidence that enhanced expression of TGF-{szligbeta} 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-{szligbeta} sub(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-{szligbeta} sub(2) expression levels in vivo and might thereby contribute to tumor progression and development of metastases. (Cancer Res 2006; 66(15): 7554-61)