Breast Cancer Therapies Reduce Risk of Alzheimer's Disease and Promote Estrogenic Pathways and Action in Brain
Worldwide an ever-increasing number of women are prescribed estrogen modulating therapies (EMTs) for the treatment of breast cancer.  In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer's disease. To address the impact of anti-estrogen therapies on risk of Alzheimer's and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer's followed by determination of EMT estrogenic mechanisms of action in neurons. In a propensity matched data set of 260,232 women with breast cancer, medical informatic analyses indicated that EMTs were associated with reduced risk of AD which was driven by patients receiving tamoxifen or aromatase inhibitors whereas raloxifene was ineffective independently validating earlier reports. Mechanistically, a comparative analysis of EMTs vs estradiol was conducted to determine whether EMTs exerted estrogenic action in neural cells in-vitro and in brain in-vivo. Outcomes of mechanistic analyses indicated that select EMTs induced estrogenic action and pathways in neural cells including promoting neuronal morphological plasticity, electrophysiological indicators of synaptic connectivity, mitochondrial number and function and induction of transcriptomic pathways consistent with estrogenic outcomes. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer's disease while simultaneously acting as effective estrogen receptor antagonists in breast. Overall design: To determine and validate the impact of SERM treatment on the CNS, 6-month-old female Sprague Dawley rats were ovariectomized and treated with EMT. Briefly, rats underwent surgery (ovariectomy or sham) at 6 months by Charles River Laboratories. After a 2-week wash-out period, rats were randomly distributed into 8 equal groups based on treatment type. Each rat was then treated according to their assignment group (i.e., SHAM, OVX+Vehicle, OVX+EMT) at clinically relevant concentrations based on allometric dose scaling (Human Equivalent Dose Conversion [mg/kg]). The resulting dosing regimen was once daily IP injections of estradiol E2 (0.16mg/kg), tamoxifen (3.23mg/kg), raloxifene (9.68mg/kg), anastrozole (4.03mg/kg), or exemestane (0.16mg/kg). Tissues of interest were collected at 7 days post onset of treatment and processed for transcriptomics.