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

这项研究计划将检验总体假设，即“高龄会影响 用于研究一种疾病的动物模型，在人类中，衰老是一个主要的风险因素“(RFA-AG-16-020)。 乳腺癌是女性的一种与年龄相关的癌症。我们将利用可诱导的基因工程小鼠 乳腺上皮细胞靶向雌激素受体α(ESR1)和芳香酶模型(GEMM) (CYP19A1A)过表达以检验研究特异性假说：“ERα和/或芳香酶的诱导 老龄小鼠乳腺上皮细胞过度表达对乳腺发育的影响 诱导和/或改变对预防性药物的应答概率后的癌前病变和癌症 他莫昔芬和/或来曲唑。GEMM将用于平行人类乳腺癌的进展，因为 人类乳房ERα和芳香酶表达增加也与乳腺癌的发生有关 女性癌前病变导管增生、导管原位癌和浸润性癌。具体目标：1. ESR1或CYP19A1开始表达的年龄是否影响乳腺发育 创业与癌症？当小鼠出生到12、18或24个月时，描述疾病发展的特征 在诱导ESR1或CYP19A1过表达之前。2.ESR1或CYP19A1表达的年龄 是否开始影响乳腺癌预防药物他莫昔芬和他莫昔芬的耐药性或应答率 来曲唑？他莫昔芬和来曲唑在18个月龄时使用6个月后的反应特征 暴露在转基因表达环境中。3.评估老年小鼠是否患有延迟的ESR1和/或CYP19A1 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。这项研究的意义在于，它是第一次检查ERα或ER是否影响 芳香酶的过度表达在老年动物中不同于年轻动物和/或老年动物 对他莫昔芬或来曲唑等抗激素药物的干预反应不同。目前， 大多数患乳腺癌的女性年龄较大，然而，临床前研究和许多临床研究 不包括年龄较大的研究对象。发病机制和治疗反应潜在地受年龄和 确定相关因素可以改善对老年妇女的风险评估和干预。预期 结果包括定义对疾病的影响年龄和在所研究的模型中进行干预，发展 为希望使用相同或类似模型来研究老龄化影响的其他研究人员制定的方案 关于疾病的发病机制或治疗方法，以及有助于理解乳腺癌发病率的信息 随着年龄的增长和对其可能的预防的洞察力而增加。

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.