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. Here, ESR1 is linked to breast cancer.