found that bone metastases could not form in the absence of estrogen; while supplementation with estrogen led to increased incidence and size of bone metastases in a dose-dependent manner, the osteoclast number and secretion of PTHrP are also upregulated by estrogen administration mediated by ERα, indicating that ER may serve as not only a biomarker but also a potential molecular driver in osteolysis and metastatic progression in breast cancer (26). This evidence concerns the gene ESR1 and breast carcinoma.