Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions
FIP200通过自噬和非自噬功能调控乳腺癌的机制
基本信息
- 批准号:9381905
- 负责人:
- 金额:$ 36.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-15 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAllelesAnimal ModelApoptosisAutophagocytosisBRCA1 geneBindingBiological ProcessBreast Cancer CellBreast Cancer ModelBreast Epithelial CellsBreast cancer metastasisCancer RelapseCell physiologyCellsCharacteristicsComplementComplexDNA Sequence AlterationDataDevelopmentDiseaseEmbryoEpidermal Growth Factor ReceptorFamilyGoalsGrowthHealthHomeostasisHumanImpairmentIncidenceKnock-inKnock-in MouseKnowledgeLaboratoriesMaintenanceMalignant NeoplasmsMammary NeoplasmsMediatingModelingMolecularMusMutant Strains MiceMutateMutationNeoplasm MetastasisPTK2 genePatientsPlayPopulationPropertyProteinsRecurrent diseaseRegulationRelapseRoleSignal TransductionStarvationStat3 Signaling PathwaySystemTNF geneTransforming Growth Factor Beta 2Transforming Growth Factor betaTumorigenicityWomanaldehyde dehydrogenasesantitumor effectbasecancer therapyconditional mutantgenetic analysisgenetic approachimmune functionin vivoinsightmalignant breast neoplasmmouse modelmutantneoplastic cellnovelnovel therapeuticsresponsestem-like celltargeted treatmenttooltransforming growth factor beta3tumortumor growthtumor progressiontumorigenic
项目摘要
Breast cancer is the most common malignancy among US women and remains a major health threat with
high incidence and lethality. Despite the remarkable progress made recently in deciphering the genetic
mutations associated with breast cancer, our understanding of the mechanistic basis for metastasis and
relapse of breast cancer is still very limited. The long-term goal of the proposed studies is to understand the
molecular and cellular mechanisms involved in these properties of breast cancer cells that are ultimately
responsible for patient lethality. FIP200 (FAK-family Interacting Protein of 200 kDa) was initially identified in our
laboratory and subsequently shown to be a component of the ULK1/Atg13/FIP200 complex essential for the
induction of autophagy. We have shown recently that FIP200 ablation inhibited the development and
progression of breast cancer, providing the first evidence of a pro-tumorigenic role for autophagy in animal
models with intact immune functions. We also developed an inducible system to delete FIP200 after tumor
development in vivo and demonstrated that acute disruption of autophagy by FIP200 deletion in established
tumors blocked their growth. In preliminary studies, we identified two distinct populations of breast cancer
stem-like cells (BCSCs) and showed that FIP200 ablation impaired the maintenance and tumorigenicity of both
BCSCs. Our preliminary data implicated TGF-β/Smad and EGFR/Stat3 signaling pathways in mediating
FIP200 regulation of these two BCSCs respectively. In another set of preliminary studies, we identified
residues 582-585 in FIP200 for binding to Atg13 and generated a new FIP200 knock-in mutant mouse with
these residues mutated to Ala (designated as KI allele, encoding FIP200-4A lacking binding to Atg13). Analysis
of KI/KI mice and MEFs derived from KI/KI embryos showed both autophagy and non-autophagy functions of
FIP200 in regulating different biological processes. These studies further revealed a new non-autophagy
function of FIP200 to protect normal and transformed MEFs from TNFα-induced apoptosis. Thus this unique
mutant KI allele as well as additional mouse models prepared in preliminary studies provides us with powerful
tools for the genetic analysis of mechanisms of FIP200 regulation of breast cancer through its autophagy and
non-autophagy functions in vivo. Based on these strong preliminary data and using our unique novel mouse
models, we propose to 1) determine the mechanisms of FIP200 regulation of CD29hiCD61+ and ALDH+ BCSCs
in PyMT and BRCA1-deficient mouse models of breast cancer; 2) examine autophagy and non-autophagy
functions of FIP200 in the regulation of BCSCs and breast cancer development and progression; and 3)
explore the strategies of targeting FIP200 autophagy and non-autophagy functions in BCSCs for breast cancer
therapy. Together, these studies will provide significant insights into the molecular and cellular mechanisms of
breast cancer metastasis and relapse that may contribute to novel therapies for this devastating disease.
乳腺癌是美国女性中最常见的恶性肿瘤,仍然是女性的主要健康威胁
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JUN-LIN GUAN其他文献
JUN-LIN GUAN的其他文献
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{{ truncateString('JUN-LIN GUAN', 18)}}的其他基金
Intersection of autophagy and vesicle trafficking in Her2-positive breast cancer
Her2 阳性乳腺癌中自噬和囊泡运输的交叉点
- 批准号:
10658423 - 财政年份:2023
- 资助金额:
$ 36.46万 - 项目类别:
Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions
FIP200通过自噬和非自噬功能调控乳腺癌的机制
- 批准号:
10166785 - 财政年份:2017
- 资助金额:
$ 36.46万 - 项目类别:
Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions
FIP200通过自噬和非自噬功能调控乳腺癌的机制
- 批准号:
9927485 - 财政年份:2017
- 资助金额:
$ 36.46万 - 项目类别:
Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes
自噬基因对神经干细胞和神经发生的调节
- 批准号:
10221784 - 财政年份:2015
- 资助金额:
$ 36.46万 - 项目类别:
Mechanisms of Neural Stem Cells Regulation by Autophagy
自噬调节神经干细胞的机制
- 批准号:
9001627 - 财政年份:2015
- 资助金额:
$ 36.46万 - 项目类别:
Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes
自噬基因对神经干细胞和神经发生的调节
- 批准号:
10434019 - 财政年份:2015
- 资助金额:
$ 36.46万 - 项目类别:
Regulation of neural stem cells and neurogenesis by autophagy genes
自噬基因调控神经干细胞和神经发生
- 批准号:
10047559 - 财政年份:2015
- 资助金额:
$ 36.46万 - 项目类别:
Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes
自噬基因对神经干细胞和神经发生的调节
- 批准号:
10673701 - 财政年份:2015
- 资助金额:
$ 36.46万 - 项目类别:
Genetic Analysis of FAK kinase and scaffold functions in breast cancer
乳腺癌中 FAK 激酶和支架功能的遗传分析
- 批准号:
8477152 - 财政年份:2012
- 资助金额:
$ 36.46万 - 项目类别:
Genetic Analysis of FAK kinase and scaffold functions in breast cancer
乳腺癌中 FAK 激酶和支架功能的遗传分析
- 批准号:
8907919 - 财政年份:2012
- 资助金额:
$ 36.46万 - 项目类别:
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