MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER
AR-ER 在乳腺癌激素抵抗和转移中的合作机制
基本信息
- 批准号:10113551
- 负责人:
- 金额:$ 36.26万
- 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:2017-03-07 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:Adjuvant TherapyAffectAndrogen ReceptorAndrogensAromatase InhibitorsBreast Cancer ModelBreast Cancer PatientBreast cancer metastasisCandidate Disease GeneCellsClinicalCollaborationsDatabasesDevelopmentDiagnosisDiseaseDisease ResistanceDisseminated Malignant NeoplasmDistantESR1 geneEnhancersEstrogen ReceptorsEstrogen receptor negativeEstrogen receptor positiveEstrogensEvolutionFailureGene ExpressionGene TargetingGenesGenomicsGrowthGrowth Factor ReceptorsHormonalHormonesHumanKnowledgeLigandsMaintenanceMammary NeoplasmsMediatingMembraneMetastatic breast cancerModelingMutateMutationNeoplasm MetastasisNuclear ReceptorsOutcomePathway interactionsPatient-Focused OutcomesPatientsPharmacotherapyPre-Clinical ModelReceptor Cross-TalkReceptor GeneReceptor SignalingRecurrenceRelapseResistanceResistance developmentResourcesRoleSignal TransductionSiteTamoxifenTestingTherapeuticTherapeutic InterventionUp-RegulationWomanWorkdifferential expressionepithelial to mesenchymal transitionexperiencehormone resistancehormone sensitivityhormone therapyin silicoin vivoinnovationmalignant breast neoplasmmetastatic processmigrationmutantnon-genomicnovelnovel strategiesnovel therapeutic interventionoverexpressionpredictive markerpressureprognosticpromoterreceptorrefractory cancerresistance mechanismself-renewalsuccesstargeted treatmenttherapeutic evaluationtherapy resistanttumortumor growthtumor initiation
项目摘要
Estrogen receptor (ER)-positive breast tumors are treated with endocrine therapies which specifically target the
ER. Patients can remain disease-free for many years; however, resistance to treatment eventually develops,
and the majority of women will suffer a recurrence of metastatic cancer. We hypothesized that the key to the
long-term treatment of women with ER-positive breast cancers was to focus on identifying novel mechanisms
of resistance using metastatic tumors resistant to therapy where tumor evolution and clonal selection have
occurred. We identified the androgen receptor (AR) as a new clinical target which was up regulated in
resistant, metastatic tumors. We have learned that AR functionally collaborates with ER, and that resistance
may be associated with a failure of hormone therapy to completely block both androgen and estrogen
signaling. We have also discovered that AR-overexpressing cells become metastatic in vivo. Furthermore, we
were the first to identify that the estrogen receptor ESR1 gene can be mutated in metastatic tumors; acquiring
hormone-independent and endocrine therapy-resistant functions which we hypothesize will also be impacted
by ligand-independent AR signaling. Importantly, cells with ESR1 mutations also up-regulate AR,
demonstrating a unique relationship between these mutations and AR. Our Aims are: (1) To determine if
receptor crosstalk (WT or mutant ER with AR) is a mechanism of resistance to hormonal agents, (2) To
determine whether AR employs novel nuclear receptor interactions to drive hormone resistance, and (3) To
determine AR and ESR1 mutant effects on invasion and metastasis. Key success has been made in
developing resistant models with endogenous up regulation of AR coincident with acquired resistance, and we
have already identified potential AR-mediated candidate resistance mechanisms. Undoubtedly hormone
therapy resistance in patients is multifactorial and will require combination hormonal and targeted therapy
along with knowledge of the activation status of key pathways, such as those arising from mutations in ER in
metastatic tumors. Our work will impact a large number of women with ER-positive breast cancer who recur
with therapy-resistant disease.
雌激素受体(ER)阳性的乳腺肿瘤是用内分泌疗法治疗的
项目成果
期刊论文数量(1)
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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Suzanne AW Fuqua其他文献
Suzanne AW Fuqua的其他文献
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{{ truncateString('Suzanne AW Fuqua', 18)}}的其他基金
Translational Breast Cancer Research Training Program
转化乳腺癌研究培训计划
- 批准号:
10475088 - 财政年份:2018
- 资助金额:
$ 36.26万 - 项目类别:
Translational Breast Cancer Research Training Program
转化乳腺癌研究培训计划
- 批准号:
10249135 - 财政年份:2018
- 资助金额:
$ 36.26万 - 项目类别:
MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER
AR-ER 在乳腺癌激素抵抗和转移中的合作机制
- 批准号:
9884532 - 财政年份:2017
- 资助金额:
$ 36.26万 - 项目类别:
MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER
AR-ER 在乳腺癌激素抵抗和转移中的合作机制
- 批准号:
9316124 - 财政年份:2017
- 资助金额:
$ 36.26万 - 项目类别:
Nuclear Receptor, Transcription and Chromatin Biology Program
核受体、转录和染色质生物学项目
- 批准号:
10674560 - 财政年份:2007
- 资助金额:
$ 36.26万 - 项目类别:
Nuclear Receptor, Transcription and Chromatin Biology Program
核受体、转录和染色质生物学项目
- 批准号:
10439821 - 财政年份:2007
- 资助金额:
$ 36.26万 - 项目类别:
Cancer Research Career Enhancement and Related Activities
癌症研究职业提升及相关活动
- 批准号:
10239116 - 财政年份:2007
- 资助金额:
$ 36.26万 - 项目类别:
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