Role of GATA3 in transcriptional pathways suppressing breast cancer metastasis

 描述（由申请人提供）：乳腺癌死亡的主要原因是转移。我们的研究计划主要集中在转录谱系调节因子， GATA 3. GATA 3基因是乳腺癌中第三大突变基因。GATA 3作为乳腺上皮管腔分化和维持的主要调节因子，并且GATA 3调节网络在癌症进展期间被解除调节。GATA 3状态是乳腺癌的重要预后因素。GATA 3的缺失在乳腺癌的分化丧失、恶性转化和转移能力的获得中起重要作用。具有高GATA 3表达的高分化肿瘤具有较低的转移倾向，而具有低GATA 3表达的低分化肿瘤具有较高的转移倾向。GATA 3低表达与较高的组织学分级、阳性淋巴结、较大的体积、ER和PR阴性状态、HER 2过表达和较差的预后密切相关。我们已经证明，GATA 3是一种转移抑制因子，通过其调节肿瘤细胞的分化状态以及肿瘤微环境。我们的研究项目的目标是确定转录因子GATA 3在调节乳腺癌转移中发挥作用的分子机制。在具体目标1中，我们确定了调控GATA 3表达的机制。在我们的初步研究中，我们已经确定Zeppo 2（Zpo 2，ZNF 503）和ZBTB 32作为GATA 3表达的调节因子。我们将重点关注它们作为乳腺肿瘤分化、进展和转移的诱导剂的作用。尽管大多数乳腺肿瘤表达GATA 3，但GATA 3表达降低的肿瘤细胞具有更未分化的基础表型和更高的转移率。在特定目标1中，我们将使用染色质免疫沉淀，然后进行测序（ChIP-Seq）分析，以发现小鼠和人类乳腺癌中的GATA 3靶点。然后，我们将研究这些GATA 3靶基因有助于GATA 3的调节功能的机制。在具体目标2中，我们将研究转录网络如何调节GATA 3表达，重点是ZNF 503/Zeppo 2轴。由于GATA 3是乳腺癌分化的关键调节因子和转移的抑制因子，因此在分子细节上了解这些功能可能会导致生物标志物和新的治疗方法。

 DESCRIPTION (provided by applicant): The primary cause of mortality in breast cancer is metastasis. Our research plan is focused primarily on the transcriptional lineage regulator factor, GATA3. The GATA3 gene is the third most mutated gene in breast cancer. GATA3 serves as a master regulator of breast epithelial luminal differentiation and maintenance and the GATA3 regulatory networks are deregulated during cancer progression. GATA3 status is an important prognostic factor in breast cancer. The loss of GATA3 plays an essential role in the loss of differentiation and the malignant conversion of breast cancer and the acquisition of metastatic capability. Well-differentiated tumors with high GATA3 expression have a lower propensity for metastasis, whereas poorly differentiated tumors with low GATA3 expression have a greater propensity for metastasis. Low GATA3 expression is strongly associated with higher histologic grade, positive lymph nodes, larger size, ER and PR negative status, and HER2 overexpression and a poorer prognosis. We have demonstrated that GATA3 is a suppressor of metastasis though its regulation of the differentiation state of the tumor cells as well as that of the tumor microenvironment. The goal of our research project is to define the molecular mechanisms through which the transcription factor GATA3 exerts its effects in regulating breast cancer metastasis. In Specific Aim 1, we determine mechanisms regulating GATA3 expression. In our preliminary studies, we have identified Zeppo2 (Zpo2, ZNF503) and ZBTB32 as regulators of GATA3 expression. We will focus on their roles as inducers of mammary tumor differentiation, progression and metastasis. Although most breast tumors express GATA3, tumor cells with decreased GATA3 expression have a more undifferentiated, basal phenotype and a higher metastatic rate. In Specific Aim 1, we will use chromatin immunoprecipitation followed by sequencing (ChIP-Seq) analysis to discover GATA3 targets in both mouse and human breast cancer. We will then investigate the mechanisms by which these GATA3-target genes contribute to GATA3's regulatory functions. In Specific Aim 2, we will investigate how the transcriptional network regulating GATA3 expression, focusing on the ZNF503/Zeppo2 axis. Since GATA3 is a critical regulator of breast cancer differentiation and suppressor of metastasis, then understanding these functions in molecular detail could lead to biomarkers and new therapeutic approaches.