ESR1 and neoplasm: Because these experiments provide the first evidence, to our knowledge, that bone anabolic effects of E2 promote ER+ BMET progression subsequent to tumor cell dissemination to bone (as bone seeding was E2- and age-independent), this finding may have clinical implications when estrogens and/or other anabolic agents are used to treat osteoporosis in post-menopausal women[75], an age where breast cancer incidence is the highest[76] and silent bone micrometastases may already be present prior to a ER+ breast cancer diagnosis[77–80].