Because mice, unlike humans, lack aromatase expression in mammary tissue and bone cells[14,15] and also have 10-fold lower circulating 17β-estradiol (E2) levels than humans[16], the optimal growth of human ER+ breast cancer orthotopic tumors and osteolytic BMETs in preclinical murine models is dependent on exogenous E2 supplementation[17,18,19–26,27,28]. Here, ESR1 is linked to breast cancer.