Transcriptional regulation of breast cancer metastasis

描述(申请人提供)：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。乳腺癌的主要死亡原因是转移，这一过程仍然知之甚少，而且仍然不可能准确预测患者转移形成的风险。细胞命运的指定是通过建立转录因子的分级网络来实现的。我们已经证明，GATA-3在维持成人乳腺管腔细胞命运中起着重要作用，GATA-3可能在管腔乳腺癌的发病机制中起着因果作用。在父母的资助中，我们正在测试GATA-3维持乳腺肿瘤分化的假设，以及它的缺失在恶性进展中起因果作用的假设。我们现已鉴定出Zeppo1(Znf703)和Zeppo2(Znf503)是GATA-3调控下游的新的锌指基因。重要的是，Zeppo1是位于染色体8p11-12的扩增子中的一个基因，存在于约25%的人类乳腺癌中，它与细胞增殖和肿瘤分级的增加以及无转移患者生存期的降低有关。在这一竞争性修订中，我们建议通过创造就业来刺激经济，以实现确定Zeppo1作用机制的新科学目标。我们建议通过在正常和致瘤的小鼠乳腺上皮细胞的三维器官培养中过表达或敲除Zeppo1，并检测细胞与细胞的黏附、迁移和细胞迁移，来确定Zeppo1作为细胞黏附、迁移和极性调节因子的作用机制。我们将确定Zeppo1过表达是否会增加乳腺癌小鼠模型的转移。这些研究将通过对比GATA3丢失更晚的进程影响过程的基因提供重要的、新的见解来加速对肿瘤转移的转录调控的理解。通过雇用更多的科学工作人员，这些竞争性的修订基金将促进在两年资助期内可以进行调查的研究。。 公共卫生相关性：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。这项研究解决了女性健康的一个重要方面，即在人类乳腺癌中扩增的Zeppo1基因如何调节乳腺癌的进展和转移。如果我们能在转移性肿瘤中阻止Zeppo1的增加或使其失活，我们将极大地改善乳腺癌的预后，拯救数百万女性的生命。这些研究可能形成乳腺癌干预和治疗的基础，潜在地防止乳腺癌病变的转移。

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. The primary cause of death in breast cancer is metastasis, a process that is still poorly understood, and it is still not possible to accurately predict the risk of metastasis formation in patients. The specification of cell fate occurs through the establishment of hierarchical networks of transcription factors. We have shown that GATA-3 plays a fundamental role in the maintenance of the luminal cell fate in the adult mammary gland and that GATA-3 may be playing a causal role in the pathogenesis of luminal mammary cancer. In the parent grant, we are testing the hypothesis that GATA-3 maintains the differentiation of breast neoplasms, and that its loss plays a causal role in malignant progression. We have now identified Zeppo1 (Znf703) and Zeppo2 (Znf503) as novel zinc finger genes downstream of GATA-3 regulation. Importantly, Zeppo1 is a gene in the amplicon on chromosome 8p11-12 is present in ~25% of human breast cancers and is associated with increased cell proliferation and tumor grade, and a reduction in metastasis-free patient survival. In this competitive revision, we propose to stimulate the economy through job creation to accomplish the new scientific objective of determining the mechanism of action of Zeppo1. We propose to determine the mechanism of action of Zeppo1 as a regulator of cell adhesion, migration and polarity in mammary epithelial cells, by overexpressing or knocking down Zeppo1 in three- dimensional organotypic cultures of normal and tumorigenic mouse mammary epithelial cells and examine cell-cell adhesion, polarity and cell migration. We will determine whether Zeppo1 overexpression increases metastases in a mouse model of breast cancer. These studies will accelerate the understanding of the transcriptional regulation of tumor metastasis by providing significant, new insights into genes that affect processes later in progression than the loss of GATA3. By enabling the hiring of additional scientific staff, these competitive revision funds will facilitate studies that are amenable to investigation within the two-year funding period. . PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, that of how Zeppo1, a gene amplified in human breast cancer regulates breast tumors progression and metastasis. If we could prevent the increase of Zeppo1 or inactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women. These studies may form the basis of intervention and therapy in breast cancer, potentially preventing breast cancer lesions from metastasizing.