Aging-associated mammary cancer-initiating cells

与衰老相关的乳腺癌起始细胞

• 批准号: 10292285
• 负责人: LUZHE SUN
• 金额: $ 38.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10292285
• 关键词: Age; Aging; Basal Cell; Biological Markers; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Epithelial Cells; CDKN2A gene; Cell Aging; Cells; Clinical Research; Clinical Trials; DNA Damage; Data; Dose; Epithelial Cells; Exposure to; Feedback; Foundations; Frequencies; Functional disorder; Future; Gene Expression Profile; Gene set enrichment analysis; Genes; Gland; Goals; Human; Hyperplasia; In Vitro; Incidence; Inflammation; Inflammatory Response; Intervention; Lead; Lesion; Mammary Duct; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mammospheres; Mediating; Molecular; Mus; Natural regeneration; Older Population; Oncogenes; Oncogenic; Ontology; Organoids; Patients; Pharmacology; Phenotype; Population; Postmenopause; Premenopause; Prevention; Prevention strategy; Publishing; RNA Splicing; Reporting; Research; Sirolimus; Stratum Basale; Stromal Cells; Sum; Testing; Variant; Woman; Work; age related; aging population; breast tumorigenesis; cytotoxic; experience; fisetin; high risk; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; mammary; mouse model; multidisciplinary; neoplastic; novel; prevent; promoter; repaired; senescence; stem; stem cells; stem-like cell; transcriptome sequencing; transdifferentiation; triple-negative invasive breast carcinoma; tumor; tumor xenograft; tumorigenesis; whole genome

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;衰老是主要风险 乳腺癌和老龄化人口在美国正在稳步扩大。这是一个没有答案的问题 很大程度上是因为与年龄相关的乳腺癌发病率增加的细胞和分子机制 发病率知之甚少。我们最近发表了CD 49 fhi乳腺干细胞的百分比 在体外可以形成基底样乳腺球并在体内再生乳腺导管的MaSCs， 在老化过程中稳定。CD 49 fhi基底样细胞的年龄相关性增加发生在管腔和基底 层，并与乳腺导管中具有前/早期肿瘤病变的百分比增加相关。 老年（25- 32月龄）小鼠的乳腺。最近的研究表明，富含MaSC的CD 49 fhi 人乳腺上皮细胞比管腔上皮细胞更容易被癌基因转化， 祖细胞和成熟管腔细胞。事实上，老年小鼠的乳腺在体内再生 CD 49 fhi MaSCs显示出比那些通过CD 49 fhi再生的细胞显著更多的增生和发育不良病变。 来自年轻（2至6月龄）小鼠的CD 49 fhi MaSC。全基因组RNA测序与基因本体 分析显示，老年小鼠中与衰老相关的炎症反应显著升高， 乳腺细胞已知衰老细胞具有增加的mTORC 1活性，这反过来可以 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了CD 49 fhi MaSC频率和与细胞凋亡相关的生物标志物。 绝经后患者乳腺组织中的衰老、炎症和增殖。这些新颖 观察使我们假设，细胞衰老和增加之间的正反馈回路， 衰老乳腺中mTORC 1活性促进CD 49 fhi转化和肿瘤发生 干细胞样细胞，这可以通过药物干预废除。在本提案中，我们将测试各种 小鼠衰老模型和人乳腺上皮细胞的原代类器官培养物， 绝经期妇女，以确定产生衰老相关的CD 49 fhi MaSCs的机制， 血统起源我们还将确定是否长期间歇性使用雷帕霉素和/或非瑟酮， 衰老清除剂可以消除异常的CD 49 fhi MaSC并预防乳腺肿瘤发生。如果成功， 我们的研究将揭示异常CD 49 fhi MaSC的谱系、它们是如何产生的以及是否 它们可以通过药物干预长期消除。这项工作将提供必要的 使用雷帕霉素样衰老抑制剂预防乳腺癌的未来临床研究的信息， 特别是三阴性乳腺癌，对此没有预防策略。