Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.

中文翻译：

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GATA3 的癌症特异性突变破坏了由雌激素受体 α、FOXA1 和 GATA3 控制的转录调控网络。

雌激素受体 (ER) 被类固醇激素 17β-雌二醇激活。雌激素受体α (ER-α) 在乳腺上皮细胞和乳腺癌中与转录因子 FOXA1 和 GATA3 形成调节网络。GATA3 是乳腺癌中最常见的突变基因之一，能够指定 FOXA1 和 ER-α 的染色质定位。在乳腺癌中发现的 GATA3 突变如何影响 ER-α 的基因组定位以及 ER-α 和 FOXA1 下游的转录网络仍不清楚。在这里，我们研究了复发性患者来源的 GATA3 突变 (R330fs) 在该监管网络上的功能。基因组分析表明 R330fs 突变体可以破坏 ER-α 和 FOXA1 的定位。由所有三个因子共同结合的基因座富含乳腺发育以及上皮细胞生物学不可或缺的基因。该基因集在培养的 GATA3 突变细胞和体内具有相似突变的肿瘤中受到差异调节。GATA3 突变细胞中 ER-α 和 FOXA1 分布的改变与染色质结构的改变有关，这导致基因表达差异。这些结果表明 GATA3 锌指 2 突变体在 ER-α 阳性乳腺肿瘤中发挥积极作用。