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.

项目概要 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 美国的乳腺癌和人口老龄化正在稳步扩大。这是一个没有答案的问题 很大程度上是因为乳腺癌与年龄相关的增加的细胞和分子机制 的发生率知之甚少。我们最近发表了 CD49fhi 乳腺干细胞的百分比 (MaSC)，可以在体外形成基底样乳腺球并在体内再生乳腺导管，增加 老化过程中稳定。 CD49fhi 基底样细胞与年龄相关的增加发生在管腔和基底细胞中 层，并且与乳腺导管中具有前/早期肿瘤病变的百分比增加相关。 年长（25 至 32 个月大）小鼠的乳腺。最近的研究表明，MaSC 富集的 CD49fhi 人类乳腺上皮细胞比管腔细胞更容易被癌基因转化 祖细胞和成熟的管腔细胞。事实上，老年小鼠的乳腺可以在体内再生 CD49fhi MaSCs 比通过再生的细胞再生的细胞表现出明显更多的增生和不典型增生病变。 来自年轻（2 至 6 个月大）小鼠的 CD49fhi MaSC。全基因组RNA测序和基因本体论 分析显示老年小鼠的衰老相关炎症反应显着升高 乳腺细胞。众所周知，衰老细胞的 mTORC1 活性增加，这反过来又可以 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 雷帕霉素治疗显着降低 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 观察结果使我们推测细胞衰老和细胞衰老之间存在正反馈循环 衰老乳腺中的 mTORC1 活性促进 CD49fhi 的转化和肿瘤发生 干细胞样细胞，可以通过药物干预消除。在这个提案中，我们将测试各种 衰老小鼠模型和人乳腺上皮细胞的原代类器官培养物 更年期妇女确定产生与衰老相关的 CD49fhi MaSC 的机制及其 血统起源。我们还将确定雷帕霉素和/或非瑟汀的长期间歇治疗是否是一种有效的治疗方法。 抗衰老剂，可以消除异常的 CD49fhi MaSCs 并预防乳腺肿瘤发生。如果成功的话， 我们的研究将揭示异常 CD49fhi 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 使用雷帕霉素类 senolytics 预防乳腺癌的未来临床研究信息， 特别是三阴性乳腺癌，目前尚无预防策略。