Transcriptome response to anti-hormonals in Esr1 and CYP19A1 genetically engineered mouse models of breast cancer risk during reproductive senescence

Reproductive senescence is an age-associated process in which reproductive capacity is reduced. In female mice this is associated with loss of oocytes and a corresponding reduction in ovarian estrogen production. Normal mammary gland development and function is linked to estrogen stimulation. In this study we utilize two genetically engineered mouse models of breast cancer risk, one with mammary-targeted conditional expression of Esr1, the RNA that encodes Estrogen Receptor alpha, and one with mammary-targeted conditional expression of CYP19A1, the RNA that encodes Aromatase, the enzyme that is responsible for estrogen synthesis from androgens to determine how reproductive senescence impacts the transcriptional response to commonly used anti-hormonals employed for breast cancer prevention, tamoxifen and letrozole. The goals of the study are, first, to test the extent to which each of these anti-hormonals alter the mammary gland transcriptome in mice undergoing reproductive senescence and, second, determine if the response is the same or different in the presence of Esr1 as compared to CYP19A1 transgene expression targeted to mammary epithelial cells. The objectives are to identify specific genes that are significantly differentially expressed genes within each model between treatment conditions control, tamoxifen and letrozole as well as between models under each of these conditions. Transcriptome comparisons between 18- and 20-month-old mice are used to identify differences between the two models as ovarian function diminishes during reproductive senescence. Transcriptome comparisons between cohorts of 20-month-old mice that received no anti-hormonal or a two-month-exposure to tamoxifen or letrozole beginning at age 18 months are used to identify similarities and differences between the two anti-hormonal treatments as well as similarities and differences between models. To investigate how the mouse mammary gland transcriptome is differentially impacted by Esr1 as compared to CYP19A1 over-expression during reproductive senescence and to determine if there is a differential impact of tamoxifen or letrozole exposure on the transcriptome with these two different breast cancer risk factors. Comparative gene expression profiling analysis of RNA-seq data from mouse mammary gland tissue from 18 and 20 month old Esr1 and CYP19A1 mice. Twenty month old mice were studied in the absence and presence of a 2-month exposure to tamoxifen or letrozole.