Transcriptome response of mouse mammary gland from age 12 to 30 months of age in Esr1 and CYP19A1 genetically engineered mouse models of breast cancer risk in the presence and absence of transgene induction

Breast cancer is an age-related cancer in women with two peaks, one at 50 and one at 70 years of age. Here we used two conditional genetically engineered mouse models of breast cancer risk to study mammary gland transcriptional changes that occur as female mice age from 12 to 30 months of age, paralleling aging from 58 to 85 years of age in women. The two models express either mammary epithelial cell-targeted Estrogen Receptor (ER) alpha (Esr1) or Aromatase (CYP19A1A) over-expression beginning at age 12 or 18 months of age. Both of these risk factors increase estrogen pathway signaling, either directly though the receptor or by increasing local estrogen production. The goals of the study are to determine how quickly significant transcriptional changes occur in the mammary gland following transgene induction, to determine how the transcriptome becomes modified as the mice age past reproductive senescence through old and very old life stages, and to identify similarities and differences in the transcriptomes between the two risk conditions at different ages and conditions. The first specific objective of this transcriptome-based study is to identify significantly differentially expressed genes within each model between different ages and times of transgene induction. This includes transcriptional changes induced by 1 week, 6, 12 and 18 months of transgene expression with transgene expression initiated at age 12 months as well as transcriptional changes induced by 1 week and 6 months of transgene expression initiated at age 18 months. The second specific objective is to compare the two models at different ages (12, 18, 24 and 30 months of age) and different transgene induction times (6, 12 and 18 months) to identify differentially expressed genes between the models. Comparative control mice from each model include age 18- and 24-month-old mice without transgene induction. Comparative gene expression profiling analysis of RNA-seq data from mouse mammary gland tissue from 12, 18, 24 and 30 month old Esr1 and CYP19A1 mice with and without transgene induction. Twenty-four month old mice were studied in the absence of transgene induction and in the presence of 12- and 6-month transgene induction. Twelve and 18 month-old-mice were studied in the absence and presence of 1-week transgene induction.