Identifying lincRNAs that Mediate PI 3 Kinase Dependent Breast Cancer
鉴定介导 PI 3 激酶依赖性乳腺癌的 lincRNA
基本信息
- 批准号:8610428
- 负责人:
- 金额:$ 18.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdvocateAffectAutomobile DrivingBiochemicalBiological AssayBiological MarkersBreast Cancer CellBreast Epithelial CellsCancer PatientCancer cell lineCatalytic DomainCell LineCell SurvivalCellsClinicalCollaborationsDataData SetDevelopmentEarly DiagnosisEpigenetic ProcessEventFormalinFrequenciesFunctional RNAGenetic TranscriptionGenomicsGoalsGrowthHumanIn Situ HybridizationIn VitroJointsKnowledgeLaboratoriesLinkMalignant NeoplasmsMammary NeoplasmsMediatingMethodsMicroRNAsModalityModificationMolecularMolecular ProfilingMutationOncogenicPIK3CA genePTEN geneParaffin EmbeddingPathway interactionsPhenotypePhosphatidylinositolsPhospho-Specific AntibodiesPhosphotransferasesPhysiologicalPrevalenceProcessRegulationResearch PersonnelRoleSamplingScreening for cancerSignal TransductionSomatic MutationTestingThe Cancer Genome AtlasTimeTissue MicroarrayTissuesUntranslated RNAXenograft procedurebasebiomedical informaticscancer cellcancer initiationcell growthcell transformationin vivoinnovationinsightinterestknock-downmalignant breast neoplasmmetaplastic cell transformationmolecular pathologymutantnovelnovel diagnosticsnovel therapeuticspublic health relevancesmall hairpin RNAtherapeutic targettranscription factortumor growthtumor progressiontumorigenesis
项目摘要
The PI 3-K signaling axis is critical for both the initiation and progression of many cancers, including breast
cancer, by promoting cancer cell survival and growth. Somatic oncogenic mutations in PIK3CA, the gene that
encodes the catalytic subunit of PI 3-K, are observed in a large proportion of cancer patients. Much is known
concerning the mechanisms by which the PI 3-K pathway promotes malignancy at the level of signaling and
transcriptional mechanisms. However, there is no information on the functional importance of large intergenic
non-coding RNAs (lincRNA) in mediating PIK3CA phenotypes associated with malignancy. This new
application responds to the FOA on 'Identifying Non-coding RNA targets for Early Detection of Cancer'. Using
two distinct computational and experimental approaches, we have identified a core set of lincRNAs that are
associated with PIK3CA activation in human breast cancer clinical samples. This represents for the first time
any identified link between PI 3-K pathway activation and lincRNAs. We have discovered a subset of lincRNAs
whose expression is directly regulated by PI 3-K in breast cancer cell lines, and also associated with a PIK3CA
gene signature in breast tumors. This finding formulates the basis for this proposal with the hypothesis that
lincRNAs are regulated by oncogenic PIK3CA in breast cancer cells and tissues, and that in turn these
lincRNAs promote PIK3CA-mediated cellular transformation both in vitro and in vivo.
In Aim 1, we propose to validate and characterize lincRNAs whose expression is regulated by PIK3CA in
breast cancer cells and tissues. We will identify lincRNAs associated with PIK3CA mutation in breast cancers
that underwent comprehensive molecular profiling as part of TCGA, and compare these with the lincRNAs that
we have identified from our experimental screen from breast epithelial cells expressing oncogenic PIK3CA, as
well as those computationally annotated from a breast tumor data set associated with a PIK3CA gene
signature. We have devised a prioritization strategy and will validate and characterize lincRNAs whose
expression is significantly positively and negatively regulated by PIK3CA. We will evaluate lincRNA expression
in breast cancer cell lines that harbor oncogenic PIK3CA mutations. In Aim 2, we will determine the
contribution of lincRNAs identified in our initial screens and those emerging from Aim 1 to phenotypes
associated PIK3CA-dependent malignancy. We will knock down specific lincRNAs in cells harboring oncogenic
PIK3CA and determine the consequence on cellular transformation and anchorage independence of growth.
We will evaluate lincRNA expression in tissue microarrays from breast cancer samples using in situ
hybridization probes, and evaluate the requirement of lincRNAs in promoting tumor growth in vivo using
xenografts. Ultimately, our studies will provide new molecular insights linking PIK3CA cancer phenotypes to
lincRNAs and thus provide a rationale for the inclusion of lincRNAs as a novel mechanism of tumorigenesis in
cancer. They will also advocate for the use of specific lincRNAs as novel biomarkers for early cancer detection.
PI 3-K信号轴对包括乳腺癌在内的许多癌症的发生和发展都至关重要
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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Alex Toker其他文献
Alex Toker的其他文献
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{{ truncateString('Alex Toker', 18)}}的其他基金
FASEB Science Research Conference: Protein Kinases and Protein Phosphorylation
FASEB 科学研究会议:蛋白激酶和蛋白磷酸化
- 批准号:
10464756 - 财政年份:2022
- 资助金额:
$ 18.92万 - 项目类别:
Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer
PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能
- 批准号:
10246864 - 财政年份:2020
- 资助金额:
$ 18.92万 - 项目类别:
Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer
PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能
- 批准号:
10677761 - 财政年份:2020
- 资助金额:
$ 18.92万 - 项目类别:
Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer
PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能
- 批准号:
10471296 - 财政年份:2020
- 资助金额:
$ 18.92万 - 项目类别:
Exploiting Metabolic Vulnerabilities in the PI3K and Akt Pathway in Cancer for Therapeutic Benefit
利用癌症 PI3K 和 Akt 通路中的代谢漏洞获得治疗效果
- 批准号:
9903255 - 财政年份:2016
- 资助金额:
$ 18.92万 - 项目类别:
Exploiting Metabolic Vulnerabilities in the PI3K and Akt Pathway in Cancer for Therapeutic Benefit
利用癌症 PI3K 和 Akt 通路中的代谢漏洞获得治疗效果
- 批准号:
9270532 - 财政年份:2016
- 资助金额:
$ 18.92万 - 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
- 批准号:
9812868 - 财政年份:2013
- 资助金额:
$ 18.92万 - 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
- 批准号:
8870311 - 财政年份:2013
- 资助金额:
$ 18.92万 - 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
- 批准号:
8559337 - 财政年份:2013
- 资助金额:
$ 18.92万 - 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
- 批准号:
8702122 - 财政年份:2013
- 资助金额:
$ 18.92万 - 项目类别:
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