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A Novel Functional Polymorphism in the Transforming Growth Factor-ß₂ Gene Promoter and Tumor Progression in Breast Cancer

Departments of ¹ Clinical Chemistry and ² Pathology, Robert-Bosch-Hospital; ³ Department of Mathematics and ⁴ Institute of Cell Biology and Immunology, University of Stuttgart; ⁵ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and ⁶ Department of Hematology and Oncology, University Medical Center, Marburg, Germany

Requests for reprints: Cornelius Knabbe, Department of Clinical Chemistry, Robert-Bosch-Hospital, Auerbachstr. 110, 70376 Stuttgart, Germany. Phone: 49-711-81013500; Fax: 49-711-81013618; E-mail: cornelius.knabbe{at}rbk.de.

Transforming growth factor-ß (TGF-ß), a multifunctional growth factor, plays an important role in breast cancer. There is increasing evidence that enhanced expression of TGF-ß 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-ß₂ 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-ß₂ expression levels in vivo and might thereby contribute to tumor progression and development of metastases. (Cancer Res 2006; 66(15): 7554-61)