The subsequent section delineates the principal signaling cascades such as transforming growth factor-beta (TGF-β), BMP-SMAD, Hippo, and ERα-Src-p190 RhoGAP that govern the pathophysiology of ER+ breast cancer bone metastasis and elucidates the pivotal regulatory proteins that serve as integrative nodes within these interconnected networks. The gene discussed is ESR1; the disease is breast cancer.