Increased osteolytic BMET lesion size in E2-treated (vs. control) mice inoculated with ER− breast cancer cells further confirmed a role of anabolic bone microenvironmental effects of E2 in driving osteolytic breast cancer BMET progression, independent of tumoral ER signaling, consistent with previous similar reports in ER− BMET models[35,36]. This evidence concerns the gene ESR1 and breast cancer.