Impact of aging on progression and prevention of mammary preneoplasia and cancer

衰老对乳腺肿瘤前期和癌症的进展和预防的影响

• 批准号: 9353743
• 负责人: Priscilla A. Furth
• 金额: $ 7.54万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353743
• 关键词: Aftercare; Age; Age-Years; Aging; Animal Model; Animals; Aromatase; Aromatase Inhibitors; Biological Markers; Breast; Breast Epithelial Cells; CYP19A1 gene; Cancerous; Clinical; Clinical Research; Development; Disease; Elderly; Elderly woman; Estrogen Receptor alpha; Exposure to; Funding; Genetic Enhancement; Genetic Transcription; Genetically Engineered Mouse; Genotype; Gland; Hormonal; Human; Incidence; Intervention; Intraductal Hyperplasia; Lead; Lesion; Letrozole; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Medicine; Modeling; Mus; Noninfiltrating Intraductal Carcinoma; Organ; Outcome; Pathogenesis; Patients; Peer Review; Pike fish; Premalignant; Prevalence; Prevention; Preventive; Preventive therapy; Probability; Publishing; Reporting; Research; Research Personnel; Resistance; Review Literature; Risk Assessment; Risk Factors; Study models; TP53 gene; Tamoxifen; Testing; Time; Toxic effect; Transgenes; Universities; Walkers; Woman; Work; age related; aged; cancer invasiveness; cancer type; cohort; comparative; improved; insight; juvenile animal; malignant breast neoplasm; mammary gland development; metaplastic cell transformation; mouse model; older women; overexpression; preclinical study; prepuberty; protocol development; response; therapy outcome; transcriptome; transcriptome sequencing; transgene expression; treatment response; tumor progression; young adult

The research plan will test the overall hypothesis that “Advanced age impacts the experimental outcomes of the animal model used to study a disease that, in humans, has aging as a major risk factor” (RFA-AG-16-020). Breast cancer is an age-related cancer in women. We will utilize inducible genetically engineered mouse models (GEMMs) of mammary epithelial cell-targeted Estrogen Receptor (ER) alpha (Esr1) and Aromatase (CYP19A1A) over-expression to test the study-specific hypothesis: “Induction of ER alpha and/or aromatase over-expression in mammary epithelial cells of older aged mice impacts development of mammary preneoplasia and cancer following induction and/or alters the probability of response to preventive agents tamoxifen and/or letrozole.” The GEMM to be used parallel human breast cancer progression because increased ERα and Aromatase expression in the human breast also are associated with development of preneoplastic ductal hyperplasia, ductal carcinoma in situ, and invasive cancer in women. Specific Aims: 1. Does the age at which Esr1 or CYP19A1 expression is initiated influence development of mammary preneoplasia and cancer? Characterize disease development when mice are aged to 12, 18 or 24 months before induction of Esr1 or CYP19A1 overexpression. 2. Does the age at which Esr1 or CYP19A1 expression is initiated influence the probability of resistance or response to breast cancer preventives tamoxifen and letrozole? Characterize response to tamoxifen and letrozole administered at age 18 months after six months exposure to transgene expression. 3. Evaluate whether or not older mice with delayed Esr1 and/or CYP19A1 transgene induction are better models for human breast preneoplasia and cancer development and/or therapy study. Significance of the study is that it is a first examination of whether or not the impact ER alpha or aromatase over-expression is different in older as compared to younger animals and/or whether older animals respond differentially to intervention with an antihormonal agent such as tamoxifen or letrozole. At present the majority of women who develop breast cancer are older however preclinical studies and many clinical studies have not included older subjects. Pathogenesis and therapeutic response are potentially impacted by age and identification of relevant factors could improve risk assessment and intervention in older women. Expected results include definition of the impact age on disease and intervention in the models studied, development of protocols for other investigators who wish to use the same or similar models for studying the impact of aging on disease pathogenesis or therapy, and information that will aid in understanding why breast cancer incidence increases with age and insight into its possible prevention.

研究计划将检验总体假设，即“高级年龄影响 该动物模型用于研究一种疾病，在人类中，衰老是主要的危险因素”（RFA-AG-16-020）。 乳腺癌是女性与年龄有关的癌症。我们将利用诱导的基因工程鼠标 乳腺上皮细胞靶向雌激素受体（ER）α（ESR1）和芳香酶的模型（GEMM） （CYP19A1A）过表达以检验研究特定假设：“ ERα和/或芳香酶的诱导 老年小鼠乳腺上皮细胞的过表达影响乳腺的发展 诱导和/或改变对预防剂的反应可能性后的肿瘤和癌症 他莫昔芬和/或letrozole。 人乳腺中的ERα和芳香酶表达增加也与 女性的肿瘤性导管增生，导管癌和侵入性癌症。具体目的：1。 ESR1或CYP19A1表达的年龄是否会影响乳腺的发展 肿瘤和癌症？当小鼠年龄为12、18或24个月时，疾病发展的特征 在诱导ESR1或CYP19A1过表达之前。 2。会表达ESR1或CYP19A1的年龄 启动会影响抗药性或对乳腺癌反应的可能性阻止他莫昔芬和 letrozole？六个月后18个月以18个月的年龄给予的他莫昔芬和letrozole的反应表征 暴露于转化表达。 3。评估是否延迟ESR1和/或CYP19A1的老鼠是否会 转基因诱导是人类乳腺癌和癌症发展和/或治疗的更好模型 学习。该研究的意义是，这是对影响ER alpha或 与年轻动物相比，年龄较大的芳香化酶过表达不同和/或年龄较大的动物。 对与他莫昔芬或letrozole这样的抗原剂剂的干预措施的反应不同。目前 大多数患乳腺癌的妇女都是较老的临床前研究和许多临床研究 尚未包括较旧的主题。发病机理和热反应可能受年龄的影响， 识别相关因素可以改善老年妇女的风险评估和干预。预期的 结果包括对研究模型中对疾病和干预的影响的定义，开发 希望使用相同或相似模型研究衰老影响的其他研究人员的协议 关于疾病的发病机理或治疗，以及将有助于理解乳腺癌发生率的信息 随着年龄的增长并深入了解其可能的预防。