ESR2 and breast cancer: Possible explanations for the partial ICI agonism are: 1) lack of ERα protein down-regulation, as observed in cells of the sheep uterus or in human breast cancer cells; 2) species-specific differences in the N- or C-terminal regions of ERs, which could influence ligand discrimination; 3) ER activation via non-classical mechanisms (e.g. non-genomic actions and indirect activation at AP-1 promoters); 4) ICI activation of other ER subtypes (nuclear ERβ or membrane ERs) or ER variant proteins whose relative expression depends on the cell type or species [36-40].