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.

Breast cancer is an age-related cancer with most patients developing disease after age 50. This proposal will explore how hormonal factors that are deregulated in mammary glands of aged mice might lead to the development of mammary cancer and how the aged gland responds to anti-hormonal preventive therapy.