A novel functional polymorphism in the transforming growth factor-β2 gene promoter and tumor progression in breast cancer
A novel functional polymorphism in the transforming growth factor-β2 gene promoter and tumor progression in breast cancer
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DOI：
10.1158/0008-5472.can-06-0634
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Knabbe, Cornelius
中科院分区：
文献类型：
--
作者：
Beisner, Julia;Buck, Miriam B.;Knabbe, Cornelius
转化生长因子-β (TGF-β) 是一种多功能生长因子，在乳腺癌中发挥着重要作用。越来越多的证据表明，TGF-β 表达的增强会促进乳腺癌进展，从而导致肿瘤的转移和侵袭。我们在 TGFB2 启动子中发现了一个功能多态性，即在相对于转录起始位点（-246ins）的-246位置插入了 4 bp。瞬时转染实验表明-246ins多态性显着增加乳腺癌细胞中TGFB2启动子活性。电泳迁移率变动分析揭示了转录因子 Sp1 与 -246ins 等位基因的结合。 Sp1 的过度表达增强了 -246ins 等位基因的启动子活性，表明 Sp1 介导转录激活。此外，-246ins 等位基因与乳腺癌组织中 TGF-β(2) 表达增强相关 (P = 0.0005)。为了评估多态性在乳腺癌中的作用，确定了乳腺癌患者 (n = 78) 和健康女性对照 (n = 143) 中 -246ins 等位基因的频率。没有发现显着差异。然而，-246ins 等位基因的存在与淋巴结转移相关（P = 0.003）。在多变量 Logistic 回归分析中，-246ins 等位基因是淋巴结转移的重要预测因子，与雌激素和孕激素受体状态无关（P = 0.0118，比值比，5.18；95% 置信区间，1.44-18.62）。我们提供的证据表明，TGFB2 -246ins 多态性导致体内 TGF-β(2) 表达水平增强，从而可能有助于肿瘤进展和转移的发生。
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.