Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms

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.

Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation

“…26,34 Clinical data obtained from a phase 2 clinical trial show that E4 has a lower impact on coagulation than 17ebeta-estradiol or E2 and, thus, might have minimal impact on thromboembolic events. 21 Moreover, recent studies reported that E4 has interesting properties on breast tissue, 35,36 and we sought herein to evaluate extensively its effects on the vagina. We demonstrate that a chronic E4 treatment has a morphological and functional impact on the vagina of mice similar to that elicited by E2.…”

Accurate Control of 17β-Estradiol Long-Term Release Increases Reliability and Reproducibility of Preclinical Animal Studies

“…Four days before cancer cell injection, mice were implanted s.c. either with a 1.7 mg/60 days MP or with a ME2/60 days RI, or were sham operated (untreated control group). Human adenocarcinoma MCF7 cells were used as previously described [ 14 ]. Tumor cells (1 × 10 6 cells suspended in 200 μl of Matrigel) were injected s.c. to both flanks of mice.…”

Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women

“…Since E4 does not bind to SHBG and has no active metabolites [3,5], it may be feasible to dose future E4 treatment individually based on blood levels of E4. Importantly, as described in the Introduction, data from in vitro and in vivo studies and a first clinical study in women with recently diagnosed breast cancer [11][12][13]35] show that E4 has mixed agonistic and antagonistic effects on the breast, which may result in a favorable profile in relation to the risk of breast cancer. Altogether, in the author's opinion the emerging profile of E4 may be best summarized as that of a "Natural SERM" (selective estrogen receptor modulator).…”

“…In vitro studies in human breast cancer cell lines showed that E4 is a weak estrogen agonist, but in the presence of E2, E4 behaves as an antagonist on the breast [11][12][13]. Dimethylbenzanthracene (DMBA) in vivo studies showed that E4 is able to prevent breast tumor development in a dose-dependent way and also caused regression of existing tumors in this model dose-dependently [14].…”