Abstract
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.
Highlights
Menopausal complaints such as hot flushes, sexual and sleep disorders or loss of bone mineral density are usually relieved by the administration of an estrogen [1]
Dose-response curves for E2 and E4 recorded in the E-Screen assay (Figure 1C), showed that E4 produced a weak agonistic activity compared to E2 with an EC50 of 4x10-9M and a maximal mitogenic effect around 1x107M, demonstrating a 200 times weaker capacity to induce MCF-7 BOS cell growth than E2 (EC50 = 2x10-11M)
The identification of new estrogenic compounds for menopausal hormone therapy (MHT) that selectively preserve the beneficial effects of estrogens while reducing their unwanted side effects, such as breast cancer promotion, is largely needed
Summary
Menopausal complaints such as hot flushes, sexual and sleep disorders or loss of bone mineral density are usually relieved by the administration of an estrogen [1]. Menopausal hormone therapy (MHT) has been associated with severe side effects Due to their strong hepatic impact, estrogens increase the incidence of thromboembolic events [2,3,4]. The administration of an estrogen combined with progestin increases the risk of breast cancer [3, 5,6,7] These observations highlight the need to develop new MHT with safer compounds that retain the beneficial effects of estrogens on the bone, uro-genital and central nervous systems, while exhibiting minimal impact on hepatic and mammary tissues. Several animal and in vitro studies indicate that E4 presents a biological profile similar to selective estrogen receptor modulators (SERMs) It exhibits estrogenlike effects on the brain [9,10,11], bone [12], uterus [1315], ovulation [16] and atheroma prevention [13].
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