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
• 负责人: LUZHE SUN
• 金额: $ 39.54万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9536728
• 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; 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; immunomodulatory drugs; 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（由申请人提供）：我们的长期目标是确定如何专门预防与衰老相关的乳腺癌。这是一个未回答的问题，很大程度上是因为对与衰老相关的乳腺癌发病率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老年（22-30个月）乳腺和老年MaSC再生乳腺分别比年轻（4-6个月）乳腺和年轻MaSC再生乳腺显示出显著更多的增生灶、非典型导管增生（ADH）和导管原位癌（DCIS）。这是第一次实验证明MaSC是自发性肿瘤病变的前体，并且衰老使MaSC易于发生肿瘤转化。全基因组RNA测序和基因本体分析揭示了衰老乳腺基质细胞中显著升高的衰老相关炎症反应（SIR）和衰老MaSC中显著升高的免疫和炎症反应，这可能产生MaSC的转化特性。事实上，用抗炎/免疫调节药物雷帕霉素处理5-10天不仅使老年乳腺和老年MaSC的表型分别恢复为与年轻乳腺和年轻MaSC的表型相似，而且还导致老年MaSC的转化特性丧失。我们最近的初步数据显示，衰老与老年乳腺中自噬标志物水平的增加有关，雷帕霉素治疗没有进一步增加自噬标志物水平，这表明雷帕霉素存在下的过度自噬可能导致老年乳腺中的增生和发育不良细胞发生凋亡和/或自噬细胞死亡，而不是细胞存活和肿瘤进展。这些新的观察结果使我们假设，衰老相关的乳腺肿瘤发生可能是由于能够形成肿瘤性病变的异常MaSC的产生，并且可以通过药物干预来预防。我们将用三个具体目标来检验这个假设。尽管已知雷帕霉素可抑制乳腺癌进展，但雷帕霉素短期治疗是否可通过MaSC机制预防乳腺肿瘤发生尚不清楚。因此，在目的1中，我们提出确定短期雷帕霉素处理消除旧MaSC的转化表型的有效剂量。我们还将确定mTOR激酶抑制剂在预防小鼠中旧MaSC介导的肿瘤性病变形成中的功效。在目标2中，我们将研究雷帕霉素是否加剧自噬以引起人和小鼠DCIS细胞的自噬性细胞死亡或凋亡，以及是否减弱老年MaSC中的免疫和炎症反应以消除其转化活性。我们还将研究雷帕霉素调节的其他与年龄相关的细胞通路和过程，这些通路和过程可能导致MaSC在衰老过程中的功能障碍。在目标3中，我们将开展临床研究，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生物标志物方面的疗效。这些目标的实现将填补知识空白，并在我们对渐进性衰老过程中MaSCs介导肿瘤转化的细胞和分子机制的理解方面取得突破。它还将为今后预防与衰老有关的乳腺癌的干预治疗和/或非治疗试验的临床研究奠定基础，这将特别有利于乳腺癌高危人群。