Different mechanisms can lead to this ligand-independent activity, the most frequent alterations are (i) the acquisition of mutations rendering ERα constitutively active; (ii) epigenomic and post-translational changes in the ERα; (iii) the activation of ERα by oncogenic intracellular signaling pathways such as PI3K/AKT, and Ras/MAPK as well as growth factors (EGFR, HER2, IGF1R, FGFR), which are themselves deregulated in cancer cells; (iv) an increase in the interaction of ERα with coactivators, at the expense of its corepressors [135]. The gene discussed is ERBB2; the disease is cancer.