Estetrol; Breast Cancer; Hormone Replacement Therapy
Abstract :
[en] The increased risk of breast cancer and thromboembolism in women who take Hormone
Replacement Therapy (HRT) currently is a major public health problem. The discovery of
novel molecules with better safety profile would provide useful advances for patient care.
Estretrol (E4) appears as a promising candidate for HRT. Indeed, in contrast to current
treatment containing ethinyl estradiol or estradiol (E2), E4 has a minimal impact on liver cells
activity supporting a decreased incidence on thromboembolic events. In preclinical studies,
E4 has been effective against the main symptoms of menopause such as hot flushes, vaginal
atrophy, and osteoporosis, from a starting dose of 0.3 mg/kg/day. The aim of this study was to
define the impact of E4 on mammary gland and breast cancer development when it is used at
concentrations effective for menopause symptom relief. We report preclinical data showing
that E4 is less efficient than E2 to induce mammary gland growth. Treatment of estrogen
receptor (ER)-positive breast cancer with several concentrations of E4 has shown that 0.3
mg/kg/day E4 did not increase tumor development. However, at 3mg/kg/day, E4 increased the
growth of hormone-dependent tumors and their metastatic dissemination in ovariectomized
and intact mice. This effect was similar to the one observed with E2 used at 0.08 mg/kg/day.
E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on
breast cancer by decreasing the strong proliferative effect of E2. While 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 extranuclear
signaling pathways 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.
In conclusion, our results support that E4, if it is used in strictly controlled clinical
applications, could have no or only limited impact on breast and breast cancer.
Disciplines :
Oncology
Author, co-author :
Gérard, Céline ; Université de Liège > R&D Direction : Chercheurs ULiège en mobilité
Gallez, Anne ; Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Blacher, Silvia ; Centre Hospitalier Universitaire de Liège - CHU > Centre d'oncologie
Noël, Agnès ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Silva, Elisabete; Institute of Environment, Health and Societies, Brunel University London, UB83PH Uxbridge, United Kingdom
Gompel, Anne; INSERM U 938, Gynaecological Endocrinology Unit, Paris Descartes University, Hôpitaux Universitaires, F-75014 Paris, France
Lenfant, Françoise; INSERM U1048, Institut des maladies métaboliques et cardiovasculaires, University of Toulouse, UPS, Toulouse, France
Arnal, Jean-François; INSERM U1048, Institut des maladies métaboliques et cardiovasculaires, University of Toulouse, UPS, Toulouse, France
Foidart, Jean-Michel ; Université de Liège > Département des sciences cliniques > Département des sciences cliniques
Pequeux, Christel ; Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Language :
English
Title :
Estetrol, a natural SERM exhibiting combined estrogenic and antiestrogenic properties on mammary gland and breast cancer
