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.
项目摘要
我们的长期目标是确定如何预防与年龄相关的乳腺癌;老龄化是主要风险。
美国的乳腺癌和老龄化人口正在稳步增长。这是一个悬而未决的问题
这在很大程度上是因为乳腺癌年龄相关性增加背后的细胞和分子机制
人们对发病率知之甚少。我们最近发表了CD49fhi乳腺干细胞的百分比
在体外形成基底样乳房并在体内再生乳腺导管的MASCs增加
在老化过程中保持稳定。CD49fhi基底样细胞的增龄性增加发生在腔内和基底部
与乳腺导管癌前病变/早期病变的百分比增加有关
老年(25至32个月龄)小鼠的乳腺。最近的研究表明,MASC富含CD49fhi
人乳腺上皮细胞更容易被癌基因转化
祖细胞和成熟腔细胞。事实上,老年小鼠体内的乳腺是再生的。
CD49fhi MASCs显示的增生性和异常增生性病变明显多于
CD49fhi MASCs来源于2~6月龄小鼠。全基因组RNA测序与基因本体论
分析显示老年小鼠衰老相关的炎症反应显著增加
乳腺细胞。已知衰老细胞mTORC1活性增加,进而可以
促进衰老相关的分泌表型。值得注意的是,在我们的临床试验中,短期低剂量
雷帕霉素治疗显著降低CD49fhi MASC频率和与细胞相关的生物标志物
绝经后患者乳腺组织的衰老、炎症和增殖。这些小说
观察结果让我们假设,细胞衰老和细胞数量增加之间存在正反馈循环
衰老乳腺组织中mTORC1活性促进CD49fhi转化和致瘤
干细胞样细胞,可以通过药物干预来消除。在这份提案中,我们将测试各种
小鼠衰老模型及原代培养人乳腺上皮细胞的实验研究
更年期妇女识别产生与衰老相关的CD49fhi MASCs的机制及其
血统起源。我们还将确定雷帕霉素和/或非赛汀的长期间歇治疗是否有
增敏剂,可消除CD49fhi MASCs的异常,防止乳腺肿瘤的发生。如果成功,
我们的研究将揭示异常CD49fhi MASCs的谱系,它们是如何产生的,以及它们是否
它们可以通过药物干预被长期废除。这项工作将提供必要的
未来使用雷帕霉素类感光物质预防乳腺癌的临床研究信息,
特别是三重阴性乳腺癌,没有预防策略。
项目成果
期刊论文数量(0)
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专利数量(0)
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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:
8535764 - 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:
8843434 - 财政年份:2012
- 资助金额:
$ 37.43万 - 项目类别:
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