GATA5 activation of the progesterone receptor gene promoter in breast cancer cells is influenced by the+331G/A polymorphism
GATA5 activation of the progesterone receptor gene promoter in breast cancer cells is influenced by the+331G/A polymorphism
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DOI：
10.1158/0008-5472.can-05-2715
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
De Vivo, I
中科院分区：
文献类型：
--
作者：
Huggins, GS;Wong, JYY;De Vivo, I
以前，在孕激素受体+331G/A基因变异和乳腺癌风险之间观察到适度的关联。在这里，在护士健康研究队列中嵌套的乳腺癌病例和对照组（n = 1，322/n = 1，953）的更大样本中，我们证实了显着相关性（比值比，1.41; 95%置信区间，1.10-1.79），并提出了分子模型。在肥胖女性中，+331G/A变异与乳腺癌的相关性特别强（体重指数> 30;比值比，2.87; 95%置信区间，1.40-5.90）。为了帮助理解这种变异可能使妇女易患乳腺癌的分子机制，我们确定了附近的转录因子结合位点。该搜索预测了与该hPR多态性相邻的加塔转录调节因子家族的结合位点。重要的是，我们发现GATA 3、GATA 4和GATA 6在正常乳腺组织和两种乳腺癌细胞系中表达，而GATA 5在正常乳腺组织中表达最低，在两种乳腺癌细胞系中表达更强。这一发现是相关的，因为GATA 5结合了与+331 G/A多态性相邻的位点，并激活了乳腺癌细胞中的hPR（-711至+822）-荧光素酶报告质粒。GATA 5的过表达增加了内源性hPR转录物的表达，并且GATA 5更强烈地激活了编码PR-B同种型的hPR启动子构建体。最后，包含+331A的hPR启动子构建体比包含+331G的构建体更强烈地被GATA 5激活。我们的研究结果表明，GATA 5与+331 G/A多态性相互作用，刺激乳腺细胞中hPR-B的表达，这可能有助于乳腺癌的易感性。
Previously, a modest association was observed between the progesterone receptor +331G/A gene variant and breast cancer risk. Here, in a larger sample of breast cancer cases and controls (n = 1,322/n = 1,953) nested in the Nurses' health Study cohort, we confirm a significant association (odds ratio, 1.41; 95% confidence interval, 1.10-1.79) and suggest a molecular model. The association of the +331G/A variant with breast cancer was particularly strong among obese women (body mass index > 30; odds ratio, 2.87; 95% confidence interval, 1.40-5.90). To help understand the molecular mechanism by which this variant may predispose women to breast cancer, we identified nearby transcription factor binding sites. This search predicted a binding site for the GATA family of transcriptional regulators adjacent to this hPR polymorphism. Importantly, we found GATA3, GATA4, and GATA6 are expressed in normal breast tissue and two breast cancer cell lines, whereas GATA5 is minimally expressed in normal mammary tissue and more strongly expressed in two breast cancer cell lines. This finding was relevant because GATA5 bound the site adjacent to the +331G/A polymorphism, and activated the hPR (-711 to +822)-luciferase reporter plasmid in breast cancer cells. Overexpression of GATA5 increased expression of the endogenous hPR transcript, and GATA5 more strongly activated an hPR promoter construct encoding the PR-B isoform. Finally, hPR promoter constructs including the +331A were more strongly activated by GATA5 than constructs including +331G. Our findings suggest that GATA5 interacts with the +331G/A polymorphism to stimulate hPR-B expression in mammary cells, which may contribute to breast cancer susceptibility.