ESR1 and breast carcinoma: In contrast to the other major estrogens in pregnancy, E2 and E1, approximately 90% of E3 precursors originate from the fetus and are metabolized in the placenta.16 If the positive association of ER-/PR- breast cancer risk with 16-pathway metabolites, including E3, that we observed were confirmed, it could indicate that the circulating concentrations responsible do not depend on the mother’s capacity to metabolize estrogens.