A Novel Functional Polymorphism in theTransforming Growth Factor-β2Gene Promoter and Tumor Progression in Breast Cancer

Abstract

Transforming growth factor-B (TGF-B), a multifunctional growth factor, plays an important role in breast cancer. There is increasing evidence that enhanced expression of TGF-B 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 À246 relative to the transcriptional start site (À246ins). Transient transfection experiments showed that the À246ins polymorphism significantly increased TGFB2 promoter activity in breast cancer cells. Electrophoretic mobility shift assays revealed binding of the transcription factor Sp1 to the À246ins allele. Overexpression of Sp1 enhanced promoter activity of the À246ins allele, demonstrating that Sp1 mediates transcriptional activation. Furthermore, the À246ins allele was associated with enhanced TGF-B 2 expression in breast cancer tissue (P = 0.0005). To evaluate the role of the polymorphism in breast cancer, frequency of the À246ins 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 À246ins allele was associated with lymph node metastasis (P = 0.003). The À246ins 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 À246ins polymorphism leads to enhanced TGF-B 2 expression levels in vivo and might thereby contribute to tumor progression and development of metastases. (Cancer Res 2006; 66(15): 7554-61)

Developmental transcriptome analysis and identification of genes involved in formation of intestinal air-breathing function of Dojo loach, Misgurnus anguillicaudatus

“…MAPKs consist of growth factor-regulated extracellular signal-related kinases (ERKs), and the stress-activated MAPKs, c-jun NH2-terminal kinases (JNKs) and p38 MAPKs21. Genes encoding components of TGF-β signaling pathway, including ligands TGF-β1 and TGF-β2 as well as receptor TGFBRI, are functionally polymorphic in humans22. TGF-β can regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death17.…”

Tumor suppressive microRNA-200a inhibits renal cell carcinoma development by directly targeting TGFB2

“…Moreover, TGFB can cause immunosuppression and angiogenesis through acting on the surrounding stromal cells, immune cells, endothelial, and smooth muscle cells, which makes the cancer more invasive [35]. Downregulation and the pro-oncogenic effect of TGFB2 have been reported in human cancer [36,37]. However, little is known whether TGFB2 is involved in RCC.…”

Two Faces of TGF-Beta1 in Breast Cancer

“…Amani et al [13] reported, for the first time, that the TGF- β 1 haplotype “GTGCCGC” might be associated with BC in Iranian woman. Several somatic mutations that disrupt the TGF β 1-Smad signaling pathway have been reported in human breast tumors [26, 42, 43]. These mutations may affect the different aspects of BC, including its occurrence, prognosis, progression, and metastasis.…”