Aging-associated mammary cancer-initiating cells
与衰老相关的乳腺癌起始细胞
基本信息
- 批准号:10490409
- 负责人:
- 金额:$ 37.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-17 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAgingBasal CellBiological MarkersBreast Cancer PreventionBreast Cancer Risk FactorBreast Epithelial CellsCDKN2A geneCell AgingCellsClinical ResearchClinical TrialsDNA DamageDataDoseEpithelial CellsExposure toFeedbackFoundationsFrequenciesFunctional disorderFutureGene Expression ProfileGene set enrichment analysisGenesGlandGoalsHumanHyperplasiaIn VitroIncidenceInflammationInflammatory ResponseInterventionLeadLesionMammary DuctMammary Gland ParenchymaMammary NeoplasmsMammary TumorigenesisMammary glandMammospheresMediatingMolecularMusNatural regenerationOlder PopulationOncogenesOncogenicOntologyOrganoidsPatientsPharmacologyPhenotypePopulationPostmenopausePremenopausePreventionPrevention strategyPublishingRNA SplicingReportingResearchSirolimusStratum BasaleStromal CellsSumTestingVariantWomanWorkage relatedaging populationbreast tumorigenesiscytotoxicexperiencefisetinhigh riskin vivoinhibitorinnovationmalignant breast neoplasmmammarymouse modelmultidisciplinaryneoplasticnovelpreventpromoterrepairedsenescencestemstem cellsstem-like celltranscriptome sequencingtransdifferentiationtriple-negative invasive breast carcinomatumortumor xenografttumorigenesiswhole genome
项目摘要
Project Summary
Our long-term goal is to determine how age-related breast cancer can be prevented; aging is the leading risk
for breast cancer and the aging population in the US is steadily expanding. This is an unanswered question
largely because the cellular and molecular mechanisms underlying the age-related increase in breast cancer
incidence are poorly understood. We recently published that the percentage of CD49fhi mammary stem cells
(MaSCs), which can form basal-like mammospheres in vitro and regenerate mammary ducts in vivo, increased
steadily during aging. The age-related increase of CD49fhi basal-like cells occurs in both luminal and basal
layers, and is associated with increased percentage of mammary ducts with pre-/early-neoplastic lesions in
mammary glands of older (25- to 32-month-old) mice. Recent studies showed that MaSC-enriched CD49fhi
human mammary epithelial cells are much more prone to be transformed by oncogenes than luminal
progenitor cells and mature luminal cells. Indeed, mammary glands regenerated in vivo by older mouse
CD49fhi MaSCs showed significantly more hyperplastic and dysplastic lesions than those regenerated by
CD49fhi MaSCs from young (2- to 6-month-old) mice. Whole genome RNA sequencing and gene ontology
analysis revealed a significantly elevated senescence-associated inflammatory response in older mouse
mammary gland cells. Senescent cells are known to have increased mTORC1 activity, which in turn can
promote a senescence-associated secretory phenotype. Significantly, in our clinical trial, short-term low-dose
rapamycin treatment significantly reduced CD49fhi MaSC frequency and biomarkers associated with cellular
senescence, inflammation, and proliferation in breast tissue from postmenopausal patients. These novel
observations led us to hypothesize that a positive feedback loop between cellular senescence and increased
mTORC1 activity in aging mammary gland promotes the transformation of, and tumorigenesis by, CD49fhi
stem-like cells, which can be abrogated by pharmacological interventions. In this proposal, we will test various
mouse models of aging and primary organoid cultures of human mammary epithelial cells from pre- and post-
menopausal women to identify mechanisms that generate the aging-associated CD49fhi MaSCs and their
lineage origin. We will also determine whether long-term intermittent treatment with rapamycin and/or fisetin, a
senolytic agent, can abrogate the aberrant CD49fhi MaSCs and prevent mammary tumorigenesis. If successful,
our research will reveal the lineage of the aberrant CD49fhi MaSCs, how they were generated, and whether
they can be abrogated for long-term by pharmacologic interventions. This work will provide essential
information for future clinical studies of using rapamycin-like senolytics for the prevention of breast cancer,
particularly the triple negative breast cancer, for which there is no preventive strategy.
项目总结
项目成果
期刊论文数量(0)
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LUZHE SUN其他文献
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{{ truncateString('LUZHE SUN', 18)}}的其他基金
Aging-associated mammary cancer-initiating cells
与衰老相关的乳腺癌起始细胞
- 批准号:
10292285 - 财政年份:2021
- 资助金额:
$ 37.43万 - 项目类别:
Aging-associated mammary cancer-initiating cells
与衰老相关的乳腺癌起始细胞
- 批准号:
10682483 - 财政年份:2021
- 资助金额:
$ 37.43万 - 项目类别:
Role of STEAP2 protein in hepatocarcinogenesis
STEAP2蛋白在肝癌发生中的作用
- 批准号:
10432061 - 财政年份:2020
- 资助金额:
$ 37.43万 - 项目类别:
Role of STEAP2 protein in hepatocarcinogenesis
STEAP2蛋白在肝癌发生中的作用
- 批准号:
10183205 - 财政年份:2020
- 资助金额:
$ 37.43万 - 项目类别:
Role of STEAP2 protein in hepatocarcinogenesis
STEAP2蛋白在肝癌发生中的作用
- 批准号:
10632092 - 财政年份:2020
- 资助金额:
$ 37.43万 - 项目类别:
Aging mammary stem cells and breast cancer prevention
衰老的乳腺干细胞与乳腺癌预防
- 批准号:
9536728 - 财政年份:2015
- 资助金额:
$ 37.43万 - 项目类别:
Aging mammary stem cells and breast cancer prevention
衰老的乳腺干细胞与乳腺癌预防
- 批准号:
9753963 - 财政年份:2015
- 资助金额:
$ 37.43万 - 项目类别:
Aging mammary stem cells and breast cancer prevention
衰老的乳腺干细胞与乳腺癌预防
- 批准号:
8963571 - 财政年份:2015
- 资助金额:
$ 37.43万 - 项目类别:
Effect of bisphenol A exposure on mammary stem cell function and transformation
双酚A暴露对乳腺干细胞功能和转化的影响
- 批准号:
8843434 - 财政年份:2012
- 资助金额:
$ 37.43万 - 项目类别:
Effect of bisphenol A exposure on mammary stem cell function and transformation
双酚A暴露对乳腺干细胞功能和转化的影响
- 批准号:
8535764 - 财政年份:2012
- 资助金额:
$ 37.43万 - 项目类别:
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