Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.

Estetrol (E 4 ) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E 2 ), E 4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E 4 exhibits an activity profile distinct from that of E 2 on mammary gland. Compared with E 2 , E 4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E 4 was 100 times less potent than E 2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERa (ESR1) is the main mediator of the estrogenic effect of E 4 on the breast. Interestingly, when E 4 was administered along with E 2 , it significantly antagonized the strong stimulatory effect of E 2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E 4 on mammary gland. Our results highlight that E 4 is less potent than E 2 and exhibits antagonistic properties toward the proliferative effect of E 2 on breast epithelial cells. These data support E 4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation.

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