Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer.
Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer.
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DOI：
10.1186/s13058-014-0464-0
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发表时间：
2014-11-20
期刊：
影响因子：
--
通讯作者：
Efroni S
中科院分区：
文献类型：
--
作者：
Cohen H;Ben-Hamo R;Gidoni M;Yitzhaki I;Kozol R;Zilberberg A;Efroni S
加塔结合蛋白3（GATA 3）是乳腺腔细胞分化的调节因子，并且是乳腺癌中的雌激素受体（ER）相关标志物。GATA 3的肿瘤抑制功能主要在基底样乳腺癌中得到证实。在这里，我们专注于它在管腔乳腺癌中的功能，其中GATA 3经常突变，其水平显着升高。通过ChIP-seq在正常和管腔癌乳腺细胞中鉴定GATA 3靶基因，然后检查GATA 3表达和突变对肿瘤发生相关基因和过程的影响。此外，分析了来自癌症基因组图谱的管腔型乳腺癌患者的突变和表达数据，以表征与GATA 3突变相关的遗传特征。我们发现，在肿瘤发生过程中，一些GATA 3的作用从肿瘤抑制转变为肿瘤促进，三个基因BCL 2，DACH 1，THSD 4的失调代表了癌症进展中主要的GATA 3控制过程。此外，我们确定了突变体GATA 3的活性改变，以及不同的相关遗传特征。这些特征取决于突变的功能结构域;并且对于特定亚组，与基底样乳腺癌患者共享，就治疗模式的考虑而言，基底样乳腺癌患者是临床组。GATA 3依赖性机制可能需要特别考虑患者的适当预后和治疗。本文的在线版本（doi：10.1186/s13058-014-0464-0）包含补充材料，可供授权用户使用。
GATA binding protein 3 (GATA3) is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated. GATA3 target genes were identified in normal- and luminal cancer- mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations. We show that some GATA3 effects shift from tumor suppressing to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment. The GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients. The online version of this article (doi:10.1186/s13058-014-0464-0) contains supplementary material, which is available to authorized users.
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