Breast Cancer (Auckl). 2019 May 15;13:1178223419844198. doi: 10.1177/1178223419844198. eCollection 2019.

The word apoptosis means: Apoptosis removes cells during development. It also eliminates pre-cancerous and virus-infected cells, although “successful” cancer cells manage to escape apoptosis so they can continue dividing. Apoptosis maintains the balance of cells in the human body and is particularly important in the immune system.

Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells.

Yue W¹, Verhoeven C², Bernnink HC², Wang JP¹, Santen RJ¹.

Author information

1Department of Medicine, Division of Endocrinology & Metabolism, University of Virginia Health Systems, Charlottesville, VA, USA.2Pantarhei Oncology, Zeist, The Netherlands.

Abstract

Purpose:

Postmenopausal women with estrogen receptor-positive breast cancers often respond initially to tamoxifen or aromatase inhibitor therapy. Resistance to these treatments usually develops within 12 to 18 months. Clinical studies have demonstrated that high-dose estrogen can induce regression of these endocrine-resistant tumors. However, side-effects of high-dose estradiol (E₂) or diethylstilbestrol (DES) limit their usage. Estetrol (E₄) is the most abundant estrogen during pregnancy and has a long half-life and a low potential for side-effects. Estetrol might then provide benefits similar to DES on tumor regression but with lesser toxicity.

Methods:

In this study, we systematically evaluated the effects of E₄ on cell proliferation and apoptosis in wild-type MCF-7 and long-term estrogen-deprived (LTED) MCF-7 cells and compared its effects with E₂ and estriol (E₃).

Results:

Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10^-11 to 10^-8 M. These effects of E₄ are similar to those of E₂ but require much higher doses. Differing from E₂, E₄ at 10^-12 M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E₃, acted similarly. No antagonistic effect of E₄ or E₃ against E₂ occurred when they were combined.

Conclusions:

The pro-apoptotic effects of E₄ and E₃ on LTED cells and at low doses on MCF-7 cells indicate that these steroids could be used as therapeutic agents for endocrine-resistant or sensitive breast cancer.

J Endocrinol. 2015 Jan;224(1):85-95. doi: 10.1530/JOE-14-0549. Epub 2014 Oct 30.

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.

Gérard C¹, Blacher S¹, Communal L¹, Courtin A¹, Tskitishvili E¹, Mestdagt M¹, Munaut C¹, Noel A¹, Gompel A², Péqueux C³, Foidart JM¹.

Author information

1Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.2Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.3Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France C.Pequeux@ulg.ac.be.

Abstract

Estetrol (E4) 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 (E2), E4 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 E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared with E2, E4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E4 was 100 times less potent than E2 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 ERα (ESR1) is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties toward the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation

Oncotarget. 2015 Jul 10;6(19):17621-36.

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

Gérard C¹, Mestdagt M¹, Tskitishvili E¹, Communal L², Gompel A^2,3, Silva E⁴, Arnal JF⁵, Lenfant F⁵, Noel A¹, Foidart JM¹, Péqueux C¹.

Author information

1Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.2Gynaecological Endocrinology Unit, Paris Descartes University, Hôpitaux Universitaires, Paris, France.3INSERM U938, Université Pierre et Marie Curie, Paris.4Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom.5INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, University of Toulouse, UPS, Toulouse, France.

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.