Functional analysis of Manic Fringe in the claudin-low breast cancer
Claudin低乳腺癌中Manic Fringe的功能分析
基本信息
- 批准号:8486634
- 负责人:
- 金额:$ 17.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAllelesBiological AssayBiologyBreast Cancer CellBreast Cancer TreatmentBreast CarcinomaBreedingCancer cell lineCandidate Disease GeneCell LineCellsCharacteristicsComplexDataDevelopmentDiseaseERBB2 geneEnzymesEpithelialEpithelial CellsEstrogen receptor negativeExhibitsFlow CytometryFrequenciesGene Expression Microarray AnalysisGenesGeneticGoalsHumanImmunohistochemistryKnockout MiceLeadLigandsMDA MB 231Malignant NeoplasmsMammary NeoplasmsMammary glandMigration AssayModelingMolecularMouse Mammary Tumor VirusMusMutant Strains MiceMutationNeoplasm MetastasisNotch Signaling PathwayOncogenesPathogenesisPathway interactionsPhenotypePlayProgesterone ReceptorsPublic HealthReceptor ActivationRecurrenceReverse Transcriptase Polymerase Chain ReactionRoleSignal TransductionStem cellsSystemT47DTestingTherapeuticTissuesTransplantationTumor Suppressor ProteinsWestern BlottingXenograft procedurebasecancer recurrencecancer stem cellcell typeeffective therapyepithelial to mesenchymal transitionglycosyltransferasehuman MFNG proteinimmunocytochemistryin vivoinsightknock-downmalignant breast neoplasmmouse modelnotch proteinnoveloutcome forecastoverexpressionpreventpublic health relevancereceptorstable cell linestemtriple-negative invasive breast carcinomatumor
项目摘要
DESCRIPTION (provided by applicant): Breast cancers that are triple negative for estrogen receptor, progesterone receptor, and Her2 (thereafter referred as TNBC) account for 15-20% of breast carcinomas and are notoriously aggressive, yet there is no targeted therapy against these malignancies. Basal-like (BLBC) and claudin-low (CLBC) are the two major subtypes of TNBC. CLBCs show characteristic of epithelial-to-mesenchymal transition (EMT) and are thought to originate from mammary stem cells (MaSC). Notch is a powerful regulator for stem cells as well as EMT in many tissues including the mammary gland. Most recently we have revealed that Lunatic Fringe (Lfng), one of the mammalian Fringes that modify Notch receptors and modulate Notch activation, exerts tumor suppressor function in MaSC and luminal progenitor cells. Interestingly, while Lfng expression is lowest in BLBC among various subtypes of human breast cancer, another mammalian Fringe, Manic Fringe (Mfng), shows highest expression in CLBC. Thus Fringes may differentially regulate Notch activation in different cell types of mammary epithelial hierarchy, and genetic alterations of Fringes may cause dysregulation of Notch signaling in different cells of origin, ultimately leading to different subtypes of breast cancer. While Lfng suppresses BLBC, Mfng may facilitate CLBC initiation and/or progression. Indeed, our preliminary analysis in a CLBC cell line suggests that Mfng enhances Notch4 signaling, which has been shown to regulate breast cancer stem cell activity. In this proposal, we plan to investigate Mfng roles in CLBC with the following Specific Aims: 1) Define Mfng functions using breast cancer cell lines. We will knockdown Mfng in CLBC cell lines and overexpress Mfng in non-CLBC cell lines to test for effects on Notch activation as well as EMT, cancer stem cell enrichment and its tumor initiating and metastatic capacity. 2) Identify potential downstream targets of Mfng in CLBC. We intend to perform microarray gene expression analysis in stable cell lines with Mfng knockdown or overexpression (from Aim 1), and to examine the expression of candidate genes in CLBC tissues. 3) Validate Mfng roles in CLBC mouse models. We will breed the Mfng null mice into CLBC mouse models to determine whether loss of Mfng suppresses CLBC tumor formation. We hope to obtain data to demonstrate that Mfng promotes CLBC initiation and/or progression. As a "druggable" enzyme, Mfng could be an ideal CLBC target since it affects specific cell types rather than broad impact from overall inhibition of Notch signaling. Furthermore, understanding the unique biology of CLBC and specific roles of Mfng-modulated Notch activation in CLBC will shed insight on cancer stem cell, which is thought to initiate recurrence and metastasis.
描述(由申请人提供):雌激素受体、孕激素受体和Her 2三阴性的乳腺癌(下文称为TNBC)占乳腺癌的15-20%,并且是众所周知的侵袭性,然而没有针对这些恶性肿瘤的靶向治疗。 基底细胞样(BLBC)和低密蛋白(CLBC)是TNBC的两种主要亚型。 CLBC显示上皮-间充质转化(EMT)的特征,并且被认为起源于乳腺干细胞(MaSC)。 Notch是包括乳腺在内的许多组织中干细胞和EMT的强大调节剂。 最近,我们已经发现,Lunatic Fringe(Lfng),哺乳动物修饰Notch受体和调节Notch激活的Fringe之一,在MaSC和管腔祖细胞中发挥肿瘤抑制功能。 有趣的是,虽然Lfng在人类乳腺癌的各种亚型中在BLBC中表达最低,但另一种哺乳动物边缘,躁狂边缘(Mfng),在CLBC中显示最高表达。 因此,条纹可以在不同类型的乳腺上皮细胞层次中差异调节Notch激活,并且条纹的遗传改变可能导致不同起源细胞中Notch信号传导的失调,最终导致不同亚型的乳腺癌。 虽然Lfng抑制BLBC,但Mfng可促进CLBC起始和/或进展。 事实上,我们在CLBC细胞系中的初步分析表明,Mfng增强了Notch 4信号传导,这已被证明可以调节乳腺癌干细胞活性。 在这个提议中,我们计划研究Mfng在CLBC中的作用,具体目的如下:1)使用乳腺癌细胞系定义Mfng功能。 我们将在CLBC细胞系中敲低Mfng并在非CLBC细胞系中过表达Mfng,以测试对Notch活化以及EMT、癌症干细胞富集及其肿瘤起始和转移能力的影响。 2)确定CLBC中Mfng的潜在下游靶标。 我们打算在Mfng敲低或过表达的稳定细胞系中进行微阵列基因表达分析(来自Aim 1),并检查候选基因在CLBC组织中的表达。 3)CLBC小鼠模型中的抗肿瘤作用。 我们将Mfng敲除小鼠培育成CLBC小鼠模型以确定Mfng的缺失是否抑制CLBC肿瘤形成。 我们希望获得数据来证明Mfng促进CLBC启动和/或进展。 作为一种“可药物化”的酶,Mfng可能是理想的CLBC靶标,因为它影响特定的细胞类型,而不是来自Notch信号传导的总体抑制的广泛影响。 此外,了解CLBC的独特生物学和Mfng调节的Notch激活在CLBC中的特定作用将有助于了解癌症干细胞,这被认为是引发复发和转移的原因。
项目成果
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