Human physiological serum E2 levels reach > 1 nm in premenopausal women and ~ 40 pm in postmenopausal women, suggesting that physiological E2 levels may be sufficient to inhibit growth of ER+ breast cancer cells with acquired resistance to hormone deprivation (Baird and Fraser, 1974; Iwase et al., 2013; Yao et al., 2000). This evidence concerns the gene ESR1 and breast cancer.