TGF-β signaling pathway and breast cancer susceptibility.
TGF-β signaling pathway and breast cancer susceptibility.
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DOI：
10.1158/1055-9965.epi-11-0062
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Dunning AM
中科院分区：
文献类型：
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作者：
Scollen S;Luccarini C;Baynes C;Driver K;Humphreys MK;Garcia-Closas M;Figueroa J;Lissowska J;Pharoah PD;Easton DF;Hesketh R;Metcalfe JC;Dunning AM
TGF-β是原发性肿瘤发生的抑制剂，但也被认为是晚期恶性阶段的促进剂。在此评估了标记典型TGF-β ALK 5/SMADs 2和3和ALK 1/SMADs 1和5信号传导途径中的17个基因的SNP与浸润性乳腺癌风险的关联：LTBP 1、LTBP 2、LTBP 4、TGFB 1、TGFB 2、TGFB 3、TGFBR 1（ALK 5）、ALK 1、TGFBR 2、内皮糖蛋白、SMAD 1、SMAD 2、SMAD 3、SMAD 4、SMAD 5、SMAD 6和SMAD 72。选择354个标签SNP（次要等位基因频率>0.05）用于分阶段研究设计中的基因分型，该研究使用了来自于CSTR研究的6，703个病例和6，840个对照。利用NCI波兰乳腺癌研究（PBCS）（1，966例病例和2，347例对照）的数据和乳腺癌协会联盟（BCAC）发布的数据对显着关联进行了荟萃分析。TGFB 1（rs 1982073）、TGFBR 1（rs 10512263）和TGFBR 2（rs 4522809）这三个SNP的相关性在TGFAP中被检测到;然而，在包括来自PBCS和BCAC的数据的荟萃分析中，相关性变得较弱。肿瘤亚型分析表明，TGFB 1 rs 1982073相关性可能仅限于发生孕酮受体阴性（PR-）肿瘤的风险增加（1.18（95% CI 1.09-1.28），4.1×10−5（PR状态OR异质性的P值= 2.3 × 10−4））。没有证据表明乳腺癌风险与利用ALK 1/SMADs 1和5促进血管生成的内皮特异性途径中的SNP相关。TGF-β ALK 5/SMADs 2和3信号通路的常见变异可能与特定肿瘤亚型的风险有关，该信号通路在细胞表面启动信号传导以抑制细胞增殖。亚型特异性关联需要非常大的研究来证实。
TGF-β acts as a suppressor of primary tumour initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for SNPs tagging seventeen genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signalling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6 and SMAD72. 354 tag SNPs (minor allele frequency>0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the SEARCH study. Significant associations were meta-analysed with data from the NCI Polish Breast Cancer Study (PBCS) (1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC). Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263) and TGFBR2 (rs4522809) were detected in SEARCH; however associations became weaker in meta-analyses including data from PBCS and BCAC. Tumour sub-type analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR−) tumours (1.18 (95% CI 1.09-1.28), 4.1×10−5 (P value for heterogeneity of ORs by PR status = 2.3 × 10−4)). There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilising ALK1/SMADs 1&5 that promotes angiogenesis. Common variation in the TGF-β ALK5/SMADs 2&3 signalling pathway, which initiates signalling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumour sub-types. The subtype specific associations require very large studies to be confirmed.