A novel functional polymorphism in the Transforming growth factor-β2 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, Jurgen, SCHWAB, Matthias, BRANCH, Hiltrud, ZUGMAIER, Gerhard, PFIZENMAIER, Klaus, KNABBE, Cornelius
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Gynecology. Andrology. Obstetrics; Mammary gland diseases; Medical sciences; Pharmacology. Drug treatments; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-0634

Transforming growth factor-β (TGF-β), a multifunctional growth factor, plays an important role in breast cancer. There is increasing evidence that enhanced expression of TGF-β 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-β2 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-β2 expression levels in vivo and might thereby contribute to tumor progression and development of metastases. (Cancer Res 2006; 66(15): 7554-61)