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Aging mammary stem cells and breast cancer prevention

衰老的乳腺干细胞与乳腺癌预防

基本信息

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
项目类别：
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

项目摘要

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.