A Reverse Translational Approach to Estrogen Modulating Therapies in Breast Cancer Treatment for Alzheimer’s Disease Prevention: Toward a Precision Approach to Brain Health and Disease

Alzheimer’s disease (AD) is a progressive, devastating neurodegenerative disease affecting more than 5.8 million people in the United States alone. By the year 2050, this figure is projected to increase to over 12.8 million people in the US and over 120 million people worldwide. Currently, two-thirds of individuals diagnosed with AD are women. It is well known that AD affects women at a greater rate than men and that the change in estrogen status during the perimenopausal-to-menopause transitions can be a risk factor for AD. The high global prevalence and economic impact of AD presents a significant public health challenge while the identification of therapies to prevent AD remains a challenge. With regard to AD prevention, multiple epidemiological studies indicate that estrogen hormone replacement therapy reduces the risk of AD and that estrogen biology is linked to AD pathobiology. In parallel, another disease that’s pathophysiology is driven by estrogen is breast cancer. Breast cancer is the most common cancer in women and is projected to account for almost one-third of all female cancers in 2020. The success in breast cancer treatment and increased survival rates is accompanied by long-term use of estrogen modulating therapies (EMT) (i.e. tamoxifen, raloxifene, and aromatase inhibitors) which were designed to be estrogen antagonists in systemic organs such as breast tissue. However, it is known that these therapeutics have tissue specific action and can act as antagonists or agonists at estrogen receptors in different local tissue environments. The mechanism of action in brain of these EMTs is largely unknown. As the number of women diagnosed with breast cancer increases, and their survival rates improve, the number of aging women exposed to EMT at risk for AD, will escalate. Thus, the neurological risk and benefit profiles of EMT used to both treat and prevent breast cancer recurrence could have increasing impact on neurologic health. To determine EMT effects on neurological health and associated mechanisms of action in brain, a reverse translational program of research was designed and executed. The fundamental hypothesis guiding this program of research was that estrogen modulating breast cancer therapies impact neurological health and estrogen signaling pathways in brain. We reasoned that if EMT act in brain as they do in breast, as estrogen receptor antagonists, then risk of Alzheimer’s should increase and estrogen regulated pathways will be decreased. However, if EMT act as estrogen receptor or estrogen synthesis agonists in brain, then risk of Alzheimer’s should decrease with a concomitant activation of estrogen signaling pathways. To address this hypothesis, a series of analyses were conducted using reverse translational strategies that capitalize on bioinformatic and systems biology approaches that integrate across clinical and discovery science to develop a proof-of-concept study of preventative therapeutic mechanisms in AD. First, we validated the impact of estrogen modulating therapy (EMT) on the incidence of AD in clinical populations from insurance claims datasets showing that EMT are protective against AD risk in postmenopausal women being treated for breast cancer. Next, we demonstrated that treatment with estrogen modulating therapy (EMT) result in pro-estrogen phenotypes in hippocampal neurons. Lastly, we demonstrate that EMT work to increase estrogen pathways signaling in hippocampal neurons with receptor specific affinities for each EMT subtype. Taken together, we show that EMTs are acting to increase estrogen-related actions in hippocampal brain tissue, and thus reinforcing the argument for the protective association of estrogen with AD-related outcomes