Aging-associated mammary cancer-initiating cells

与衰老相关的乳腺癌起始细胞

• 批准号: 10490409
• 负责人: LUZHE SUN
• 金额: $ 37.43万
• 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/10490409
• 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; 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；衰老是领先的风险 对于乳腺癌和美国衰老的人口正在稳步扩大。这是一个未解决的问题 很大程度上是因为乳腺癌与年龄相关的增加的细胞和分子机制 发病率很少。我们最近发表了CD49FHI乳细胞的百分比 （MASC）可以在体内形成体外形成基底样的哺乳动物，并在体内再生导管增加 衰老期间稳定。 CD49FHI基底样细胞的年龄相关增加发生在腔和基础上 层，与乳腺导管的百分比增加有关 较大的小鼠（25至32个月大的小鼠）的乳腺。最近的研究表明，富含MASC的CD49FHI 人类乳腺上皮细胞比腔内更容易被癌基因转化 祖细胞和成熟的腔细胞。实际上，乳腺由老鼠在体内再生 CD49FHI MASCS表现出的增生性和发育不良的病变比由 来自年轻（2至6个月大的）小鼠的CD49FHI MASC。整个基因组RNA测序和基因本体论 分析表明，老鼠老鼠的衰老相关炎症反应显着升高 乳腺细胞。已知衰老细胞的MTORC1活性增加，而这又可以 促进与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 雷帕霉素处理大大降低了与细胞相关的CD49FHI MASC频率和生物标志物 绝经后患者的乳房组织衰老，炎症和增殖。这些小说 观察结果使我们假设细胞衰老和增加之间的正反馈回路 MTORC1在乳腺老化的腺体中的活性促进了CD49FHI的转化和肿瘤发生 干细胞，可以通过药理学干预措施消除。在此提案中，我们将测试各种 衰老的小鼠模型和原发性器官培养物的人类乳腺上皮细胞来自前后的乳腺上皮细胞 更年期女性确定产生与老化相关的CD49FHI MASC及其机制 血统起源。我们还将确定是否长期用雷帕霉素和/或fisetin（a）进行长期间歇性治疗 鼻溶剂可以消除异常的CD49FHI MASC并预防乳腺肿瘤发生。如果成功， 我们的研究将揭示异常CD49FHI MASC的血统，它们的产生方式以及是否是否 可以通过药物干预措施将它们长期消除。这项工作将提供必不可少的 有关将雷帕霉素样鼻溶剂用于预防乳腺癌的未来临床研究的信息， 特别是三重阴性乳腺癌，没有预防策略。