ESR1 and neoplasm: Indeed, while a bone-specific hypothesis for tumoral ERα signaling driving BMET progression via mediation of tumor-associated osteolysis is straightforward, testing in pre-clinical models, where E2 supplementation is necessary to support robust progression of osteolytic BMET and a syngeneic mouse model is not available, is difficult since E2 has anabolic effects on the bone microenvironment and also clearly drives ER+ breast cancer cell proliferation, which is not unique to the bone microenvironment.