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
• 负责人: LUZHE SUN
• 金额: $ 38.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753963
• 关键词: Age; Aging; Anti-inflammatory; Apoptosis; Attenuated; Autophagocytosis; Bioinformatics; Biological Markers; Biopsy; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Carcinogenesis; Cell Death; Cell Survival; Cell physiology; Cells; Clinical Research; Data; Development; Dose; FRAP1 gene; Foundations; Frequencies; Functional disorder; Future; Generations; Genes; Goals; Human; Hyperplasia; Immune response; Immunomodulators; Incidence; Inflammatory Response; Intervention; Intervention Studies; Intraductal Hyperplasia; Knowledge; Lesion; Mammary Duct; Mammary Gland Parenchyma; Mammary Tumorigenesis; Mammary gland; Measurable; Mediating; Molecular; Mus; Natural regeneration; Neoplasms; Neoplastic Cell Transformation; Noninfiltrating Intraductal Carcinoma; Ontology; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Property; Regimen; Research; Research Personnel; Risk Factors; Sirolimus; Specimen; Stem cells; Stromal Cells; Testing; Transplantation; Treatment Protocols; Work; age effect; age related; breast cancer progression; breast tumorigenesis; cancer recurrence; dosage; efficacy testing; high risk; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; mTOR inhibition; malignant breast neoplasm; neoplastic; novel; prevent; public health relevance; senescence; stem; stem cell niche; transcriptome sequencing; tumor progression; whole genome; Age; Aging; Anti-inflammatory; Apoptosis; Attenuated; Autophagocytosis; Bioinformatics; Biological Markers; Biopsy; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Carcinogenesis; Cell Death; Cell Survival; Cell physiology; Cells; Clinical Research; Data; Development; Dose; FRAP1 gene; Foundations; Frequencies; Functional disorder; Future; Generations; Genes; Goals; Human; Hyperplasia; Immune response; Immunomodulators; Incidence; Inflammatory Response; Intervention; Intervention Studies; Intraductal Hyperplasia; Knowledge; Lesion; Mammary Duct; Mammary Gland Parenchyma; Mammary Tumorigenesis; Mammary gland; Measurable; Mediating; Molecular; Mus; Natural regeneration; Neoplasms; Neoplastic Cell Transformation; Noninfiltrating Intraductal Carcinoma; Ontology; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Property; Regimen; Research; Research Personnel; Risk Factors; Sirolimus; Specimen; Stem cells; Stromal Cells; Testing; Transplantation; Treatment Protocols; Work; age effect; age related; breast cancer progression; breast tumorigenesis; cancer recurrence; dosage; efficacy testing; high risk; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; mTOR inhibition; malignant breast neoplasm; neoplastic; novel; prevent; public health relevance; senescence; stem; stem cell niche; transcriptome sequencing; tumor progression; whole genome

 DESCRIPTION (provided by applicant): Our long-term goal is to determine how the aging-related breast cancer can be specifically prevented. This is an unanswered question largely because the cellular and molecular mechanisms underlying the aging-related increase in breast cancer incidence are poorly understood. We recently found that the percentage of mammary stem cells (MaSCs) in mouse mammary gland increases steadily with age. More significantly, both old (22-30 months) mammary glands and old MaSC-regenerated mammary glands obtained by in vivo transplantation showed significantly more foci of hyperplasia, atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) than young (4-6 months) mammary glands and young MaSC-regenerated mammary glands respectively. This is the first experimental demonstration that MaSCs are the precursors of spontaneous neoplastic lesions and aging predisposes MaSCs to neoplastic transformation. Whole genome RNA sequencing and gene ontology analysis revealed a significantly elevated senescence-associated inflammatory response (SIR) in aging mammary stromal cells and significantly elevated immune and inflammatory responses in aging MaSCs, which likely engendered the transforming property of MaSCs. Indeed, treatment with the anti-inflammatory/immune modulatory drug rapamycin for 5-10 days not only reverted the phenotypes of the old mammary glands and old MaSCs similar to those of young mammary glands and young MaSCs, respectively, but also resulted in the loss of the transforming property of the old MaSCs. Our most recent preliminary data show that aging is associated with increased levels of autophagy markers in old mammary glands, which were not further increased by rapamycin treatment suggesting that excessive autophagy in the presence of rapamycin might have caused hyperplastic and dysplastic cells in the old mammary gland to undergo apoptosis and/or autophagic cell death instead of cell survival and tumor progression. These novel observations led us to hypothesize that aging-associated mammary tumorigenesis may be due to the generation of aberrant MaSCs capable of forming neoplastic lesions and can be prevented through pharmacological interventions. We will test the hypothesis with three specific aims. Although rapamycin is known to inhibit breast cancer progression, whether short-term treatment with rapamycin can prevent mammary tumorigenesis via a MaSC mechanism is not known. Thus, in Aim 1, we propose to determine an effective dosage of short-term rapamycin treatment in abrogating the transforming phenotype of old MaSCs. We will also determine the efficacy of an mTOR kinase inhibitor in preventing old MaSC-mediated neoplastic lesion formation in mice. In Aim 2, we will investigate whether rapamycin exacerbates autophagy to cause autophagic cell death or apoptosis of human and mouse DCIS cells and attenuates immune and inflammatory responses in old MaSCs to abrogate their transforming activity. We will also investigate other age-related cellular pathways and processes regulated by rapamycin, which may cause the dysfunction of MaSC during aging. In Aim 3, we will carry out clinical studies to determine the effect of aging on human mammary stem/progenitor cell function and the efficacy of short-term rapamycin treatment in mitigating biomarkers associated with breast cancer recurrence in patients with DCIS. Completion of the proposed aims will fill knowledge gap and make a breakthrough in our understanding of the cellular and molecular mechanisms that mediate neoplastic transformation by MaSCs during progressive aging. It will also establish a foundation for future clinical studies of interventional treatment and/or non-treatment trials in preventing aging-related breast cancer, which should particularly benefit the population at high risk for breast cancer.

 描述（由适用提供）：我们的长期目标是确定如何明确预防与衰老相关的乳腺癌。这是一个未回答的问题，主要是因为对乳腺癌炎症与衰老相关的增加的细胞和分子机制知之甚少。我们最近发现，小鼠乳腺中乳腺干细胞（MASC）的百分比随着年龄的增长而稳定增加。更重要的是，通过体内移植获得的古老（22-30个月）乳腺和旧的MASC再生乳腺显示出更多的增生焦点，非典型导管性增生（ADH）的焦点，与原位（DCIS）（DCIS）（DCIS）和年轻的MASMARM MASMARMARY GLANDS MASMARRY GLANDS MARMARY GLANDS MASMARY GLANDS MARMARY GLANDS MARMARY GLANDS MARMARY GLANDS MARMARY GLANDS MARMARY GLANDS 分别。这是第一次实验证明，MASC是自发性肿瘤病变的前体，而衰老使MASC易于肿瘤转化。整个基因组RNA测序和基因本体分析表明，在衰老的乳腺基质细胞中，感应相关的炎症反应（SIR）显着升高，并且在衰老的MASC中显着升高了免疫和炎症反应，这很可能与MASCS的转化有关。实际上，用抗炎/免疫调节药物雷帕霉素治疗5-10天，不仅恢复了与年轻的乳腺和年轻MASC相似的旧乳腺和旧MASC的表型，而且还导致了旧Mascs转化特性的丧失。我们最近的初步数据表明，衰老与旧乳腺中自噬标记水平的升高有关，而雷帕霉素治疗并没有进一步增加雷帕霉素的治疗，这表明在存在雷帕霉素的情况下，过量的自噬可能导致旧乳腺的增生和异常细胞在旧的乳腺中导致旧乳腺，而不是细胞症和/或/或/或/或/或/或/或/或/或/或/或/或//或/或//或/或//或//或//或吞噬症的生存。这些新的观察结果使我们假设与衰老相关的乳腺肿瘤发生可能是由于产生了能够形成肿瘤病变的异常MASC，并且可以通过药物干预来预防。我们将以三个特定目标检验假设。尽管已知雷帕霉素抑制乳腺癌的进展，但雷帕霉素短期治疗是否可以通过MASC机制预防乳腺肿瘤发生。在AIM 1中，我们建议确定有效剂量的短期雷帕霉素治疗，以消除旧MASC的转化表型。我们还将确定MTOR激酶抑制剂在防止小鼠中旧的MASC介导的肿瘤病变形成的有效性。在AIM 2中，我们将研究雷帕霉素会加剧自噬是否会引起人和小鼠DCIS细胞的自噬细胞死亡或凋亡，并减轻旧MASC中的免疫和炎症反应以消除其转化活性。我们还将研究由雷帕霉素调节的其他年龄相关的细胞途径和过程，这可能会在衰老过程中引起MASC功能障碍。在AIM 3中，我们将进行临床研究，以确定衰老对人类乳腺干/祖细胞功能的影响以及短期雷帕霉素治疗在减轻DCIS患者乳腺癌复发相关的生物标志物中的短期雷帕霉素治疗的效率。所提出的目标的完成将填补知识空白，并在我们对介导MASC在进行性衰老过程中介导肿瘤转化的细胞和分子机制的理解中取得突破。它还将为未来的介入治疗和/或非治疗试验的临床研究奠定基础，以防止与衰老有关的乳腺癌，这应该特别受益于乳腺癌高风险的人群。