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FoxP3 as the X-Linked Breast Cancer Suppressor Gene

FoxP3 作为 X 连锁乳腺癌抑制基因

基本信息

批准号：
7656622
负责人：
Yang Liu
金额：
$ 32.16万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656622
关键词：
Address Alleles Attenuated Autoimmune Diseases BRCA2 gene Breast Breast Cancer Cell Breast Carcinoma Cancer cell line Clinical Data Development Diagnostic Neoplasm Staging Down-Regulation ERBB2 gene Epigenetic Process Experimental Models Family Gene Targeting Genes Genetic Goals Growth Human Knock-out Link Lung Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mediating Modality Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenes Outcome Prognostic Marker Prostate Proteins Repression Role SKP2 gene Sampling Somatic Mutation System Testing Tetanus Helper Peptide Therapeutic Tissue Sample Transgenic Organisms Tumor Suppressor Genes Tumor Suppressor Proteins Winged Helix Woman X Inactivation base in vitro testing in vivo interest malignant breast neoplasm man member mouse model novel prototype transcription factor

项目摘要

DESCRIPTION (provided by applicant): Although the prototypes of breast cancer suppressor genes, BRCA1 and BRCA2, have been identified, the genetic defects responsible for the majority of breast cancer remain elusive. In addition, essentially all cancer suppressor genes identified are autosomal. X-linked tumor suppressors are of great interest as one allele of these genes can be silenced by X-chromosome inactivation in women. The X-linked FoxP3 is a member of the forkhead/winged helix transcription factor family. Mutations of FoxP3 in both mice (FoxP3sf) and man result in severe autoimmune disease with early lethality. We have recently made a surprising observation that FoxP3sf/+ mice develop cancer at a high rate. The majority of the cancers are mammary carcinomas that have silenced FoxP3 but have over-expressed ErbB2. The overall goal of the project is to build on this exciting preliminary study, to reveal the significance of FOXP3 as a cancer suppressor and to understand the mechanisms by which FoxP3 control breast cancer development in the mouse and in humans. We will continue our effort to study the significance of FoxP3-mediated repression of HER-2/ErbB2 suppression in the mouse model of breast cancer. In addition to HER-2/Neu, our preliminary data also suggest Skp2 and CD24 as novel FoxP3 targets. Their relevance in mammary cancer formation will be tested in vitro 2-D and 2-D culture as well as in vivo in transgenic and knock out models. In addition, we will take a global approach to identify target genes regulated by the FOXP3 protein. Furthermore, we have found widespread down- regulation of the FOXP3 gene among human breast cancer samples. We will test the hypothesis that the two alleles of the FOXP3 locus are silenced by loss of heterozygocity (LOH) in conjunction with X-chromosomal inactivation. In those samples that we have failed to detect mutation or LOH, we will test the possibility that bi-allelic epigenetic mechanisms may be involved in silencing the FOXP3 locus. Finally, we will determine expression of HER-2, SKP2, CD24 and other potential FOXP3 targets among the human breast cancer samples in order to establish a spectrum of mechanisms by which FOXP3 controls breast cancer development. Our proposed studies will not only have the potential for establishing FOXP3 as an important breast cancer suppressor gene but also provide a genetic mechanism for the abnormal expression of the major breast cancer oncogene, HER-2, in humans as well as a molecular mechanism for a major therapeutic modality.

描述（由申请人提供）：尽管乳腺癌抑制基因BRCA1和BRCA2的原型已经被确定，但导致大多数乳腺癌的遗传缺陷仍然难以捉摸。此外，基本上所有确定的癌症抑制基因都是常染色体的。x连锁肿瘤抑制基因是非常有趣的，因为这些基因的一个等位基因可以通过女性x染色体失活而沉默。x连锁FoxP3是叉头/翼螺旋转录因子家族的成员。FoxP3在小鼠（FoxP3sf）和人体内的突变可导致严重的自身免疫性疾病，并具有早期致死率。我们最近做了一个令人惊讶的观察，FoxP3sf/+小鼠患癌症的几率很高。大多数癌症是沉默FoxP3但过度表达ErbB2的乳腺癌。该项目的总体目标是在这项令人兴奋的初步研究的基础上，揭示FOXP3作为一种癌症抑制因子的重要性，并了解FOXP3控制小鼠和人类乳腺癌发展的机制。我们将继续努力研究foxp3介导的HER-2/ErbB2抑制在乳腺癌小鼠模型中的意义。除了HER-2/Neu外，我们的初步数据还表明Skp2和CD24是FoxP3的新靶点。它们与乳腺癌形成的相关性将在体外二维和二维培养以及体内转基因和敲除模型中进行测试。此外，我们将采取全球方法鉴定FOXP3蛋白调控的靶基因。此外，我们发现FOXP3基因在人类乳腺癌样本中普遍下调。我们将验证FOXP3位点的两个等位基因因杂合性缺失（LOH）和x染色体失活而沉默的假设。在那些我们没有检测到突变或LOH的样本中，我们将测试双等位基因表观遗传机制可能参与FOXP3位点沉默的可能性。最后，我们将确定HER-2、SKP2、CD24和其他潜在的FOXP3靶点在人类乳腺癌样本中的表达，以建立FOXP3控制乳腺癌发展的机制谱。我们提出的研究不仅有可能确立FOXP3是一个重要的乳腺癌抑制基因，还将为人类主要乳腺癌致癌基因HER-2的异常表达提供遗传机制，并为一种主要的治疗方式提供分子机制。