Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival but comes with side effects that impact health and quality of life. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating several aspects of the human response. Single cell RNA sequencing reveals that tamoxifen induces widespread gene expression changes in the hypothalamus, particularly in neurons and ependymal cells. These effects are largely dependent on estrogen receptor alpha (ERa), as conditional ERa knockout ablated or reversed tamoxifen-induced changes in gene expression, thermoregulation, bone, and movement. These findings provide mechanistic insights into the effects of tamoxifen on the hypothalamus and suggest that hypothalamic ERa mediates several side effects of tamoxifen therapy. Overall design: A total of sixteen hypothalami were analyzed. Group sizes are as follows: Wild-type, control injections n = 3; Wild-type, tamoxifen injections n = 5; Esr1cKO, control injections n = 4, Esr1cKO tamoxifen injections n = 4