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

这项研究计划将测试总体假设，即“高龄影响实验结果， 用于研究疾病的动物模型，在人类中，衰老是主要风险因素”（RFA-AG-16-020）。 乳腺癌是一种与年龄相关的女性癌症。我们将利用诱导型基因工程小鼠 乳腺上皮细胞靶向雌激素受体（ER）α（Esr 1）和芳香化酶的模型（GEMM） （CYP 19 A1 A）过表达，以检验研究特定假设：“ER α和/或芳香化酶的诱导 老年小鼠乳腺上皮细胞中的过度表达影响乳腺癌的发育 诱导后的肿瘤前病变和癌症和/或改变对预防剂的反应概率 他莫昔芬和/或来曲唑。”GEMM将用于平行人类乳腺癌进展， 人乳腺中ERα和芳香化酶表达的增加也与乳腺癌的发生有关。 癌前导管增生、导管原位癌和女性浸润性癌。具体目标：1。 Esr 1或CYP 19 A1表达开始的年龄是否影响乳腺癌的发生 癌前病变和癌症表征小鼠年龄至12、18或24个月时的疾病发展 在诱导Esr 1或CYP 19 A1过表达之前。2. Esr 1或CYP 19 A1表达的年龄 开始影响对乳腺癌预防药物他莫昔芬的耐药性或反应的可能性， 来曲唑？在18个月大时，描述6个月后对他莫昔芬和来曲唑的反应 暴露于转基因表达。3.评估是否有延迟Esr 1和/或CYP 19 A1的老年小鼠 转基因诱导是人乳腺癌前病变和癌症发展和/或治疗的更好模型 study.这项研究的意义在于，它是第一次检查是否影响ER α或 芳香酶的过度表达在老年动物中与年轻动物相比是不同的，和/或老年动物是否 对抗激素药物如他莫昔芬或来曲唑的干预反应不同。目前 大多数患乳腺癌的女性年龄较大，但临床前研究和许多临床研究 不包括老年人。发病机制和治疗反应可能受到年龄的影响， 查明相关因素可改善对老年妇女的风险评估和干预。预计 结果包括定义年龄对疾病的影响和研究模型中的干预， 为希望使用相同或相似模型研究衰老影响的其他研究者提供协议 疾病发病机制或治疗，以及有助于了解乳腺癌发病率 随着年龄的增长和对可能的预防的了解而增加。

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.