A Transforming Growth Factorβ1 Signal Peptide Variant Increases Secretion in Vitro and Is Associated with Increased Incidence of Invasive Breast Cancer-猫眼课题宝

DOI：

--

发表时间：

2003-05

期刊：

Cancer Research

影响因子：

11.2

通讯作者：

中科院分区：

医学1区

文献类型：

--

作者：

A. Dunning;P. D. Ellis;S. McBride;H. L. Kirschenlohr;C. Healey;P. Kemp;R. Luben;J. Chang-Claude;A. Mannermaa;V. Kataja;P. Pharoah;D. Easton;B. Ponder;J. Metcalfe

有证据表明，转化生长因子(TGF) β作为肿瘤起始的抑制因子，但当TGF β信号通路的抗增殖作用被其他致癌突变所覆盖时，它也可以作为肿瘤进展的促进因子。在人类乳腺肿瘤中已经报道了几种破坏tgf - smad信号通路的体细胞突变。我们研究了TGFbeta1基因单核苷酸多态性（snp）与浸润性乳腺癌发病率之间的关系，在三个病例对照系列中，最多3987例患者和3867例对照，中位年龄约为50岁，范围为22-92岁。启动子SNP C-509T和T +29C信号肽SNP（编码Leu10Pro）处于强连锁不平衡状态。它们都以隐性方式与浸润性乳腺癌发病率增加显著相关[优势比：（TT与c -携带者），1.25；95%置信区间1.06-1.48；P = 0.009 (ProPro vs . Leu-carrier), 1.21；95%置信区间1.05-1.37；P = 0.01]。G-800A SNP与乳腺癌发病率无显著相关性。C-509T SNP不包含在已知的启动子调控元件的共识序列中，因此不太可能影响TGFbeta1的表达，而Leu10Pro信号肽替代可能影响TGFbeta1的分泌。用编码TGFbeta1的Pro或Leu形式的构建体转染HeLa细胞，并由巨细胞病毒启动子驱动，结果表明含有Pro at残基10的信号肽比Leu形式的分泌量增加2.8倍。这些数据表明，在上述人群样本中，编码Pro10的等位基因与TGFbeta1分泌率增加和浸润性乳腺癌发病率增加有关。据估计，3%的乳腺癌病例可归因于Pro10纯合性。

There is evidence that transforming growth factor (TGF)beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGFbeta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGFbeta-SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age approximately 50 years, and range 22-92 years. The promoter SNP, C-509T, and the T +29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGFbeta1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGFbeta1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGFbeta1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGFbeta1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity.