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See detailEstetrol, a natural SERM exhibiting combined estrogenic and anti-estrogenic properties on mammary gland and breast cancer
Gallez, Anne ULg; Gérard, Céline ULg; BLACHER, Silvia ULg et al

Poster (2016, May 30)

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would provide useful advances for patient care. Estetrol (E4) is a liver friendly promising candidate for HRT. In preclinical and/or clinical studies, E4 has been effective against the main symptoms of menopause 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. Our preclinical data show that E4 is less efficient than estradiol (E2) to induce mammary gland growth. Treatment with several concentrations of E4 has shown that E4 did not increase tumor development, when it is used at 0.3 mg/kg/day. However, at 3 mg/kg/day, E4 increased tumor growth similarly to E2 (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 extra-nuclear 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. [less ▲]

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See detailUse of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury:to combine or not to combine?
Tskitishvili, Ekaterine ULg; Pequeux, Christel ULg; Munaut, Carine ULg et al

in Oncotarget (2016)

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal ... [more ▼]

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated. The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival. In vivo pretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and antiestrogenic properties on mammary gland and breast cancer
Gérard, Céline ULg; Gallez, Anne ULg; BLACHER, Silvia ULg et al

Conference (2016, May 09)

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 ... [more ▼]

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. [less ▲]

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See detailNeonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem
Tskitishvili, Ekaterine ULg; VIELLEVOYE, Renaud ULg; Gérard, Céline et al

in Références en Gynécologie Obstétrique (2016), 17(1-1),

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation ... [more ▼]

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation, seizures and cerebral palsy, and mortality in newborns. This paper reviews the pathophysiology and current concepts of the management of neonatal HIE as well as the future potential neuroprotective strategies for attenuation of this disease. [less ▲]

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See detailImpact of estetrol on breast cancer development, metastatic dissemination and angiogenesis
Gallez, Anne ULg; Gérard, Céline ULg; BLACHER, Silvia ULg et al

Poster (2016)

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 ... [more ▼]

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 breast cancer development when it is used at concentrations effective for menopause symptom relief. Treatment of estrogen receptor (ER)-positive breast cancer-developing mice (MMTV-PyMT) with several concentrations of E4 has shown that 0.3 mg/kg/day E4 did not increase tumor development and metastasis dissemination. 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. In an in vivo model of ER-negative tumors, we observed that 3mg/kg/day E4 improved tumor growth by increasing angiogenesis, and subsequently decreasing necrosis and tumor hypoxia. In contrast, 0.3 mg/kg/day E4 did not induce any of these effects on ER-negative tumors and tumor microenvironment. In conclusion, we have shown that 0.3 mg/kg/day E4, already reported to prevent menopause symptoms, does not increase breast tumor growth, metastasis dissemination, and angiogenesis. However, similarly to E2, higher concentrations of E4 are pro-tumorous. These results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast cancer. [less ▲]

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See detailQuantitative assessment of mouse mammary gland morphology using automated digital image processing and TEB detection.
Blacher, Silvia ULg; Gérard, Céline ULg; Gallez, Anne ULg et al

in Endocrinology (2016)

The assessment of rodent mammary gland morphology is largely used to study the molecular mechanisms driving breast development and to analyze the impact of various endocrine disruptors with putative ... [more ▼]

The assessment of rodent mammary gland morphology is largely used to study the molecular mechanisms driving breast development and to analyze the impact of various endocrine disruptors with putative pathological implications. In this work, we propose a methodology relying on fully automated digital image analysis methods including image processing and quantification of the whole ductal tree and of the terminal end buds (TEB) as well. It allows to accurately and objectively measure both growth parameters and fine morphological glandular structures. Mammary gland elongation was characterized by two parameters: the length and the epithelial area of the ductal tree. Ductal tree fine structures were characterized by: 1) branch end-point density, 2) branching density and 3) branch length distribution. The proposed methodology was compared to quantification methods classically used in the literature. This procedure can be transposed to several software and thus largely used by scientists studying rodent mammary gland morphology. [less ▲]

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See detailEstetrol : a new natural estrogen providing a safe therapeutic window for the treatment of menopause
Gérard, Céline ULg; Gallez, Anne ULg; Silva, Elisabete et al

Poster (2015, November 14)

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would provide useful advances for patient care. Estetrol (E4) is a liver friendly promising candidate for HRT. In preclinical and/or clinical studies, E4 has been effective against the main symptoms of menopause 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. Our preclinical data show that E4 is less efficient than estradiol (E2) to induce mammary gland growth. Treatment with several concentrations of E4 has shown that E4 did not increase tumor development, when it is used at 0.3 mg/kg/day. However, at 3 mg/kg/day, E4 increased tumor growth similarly to E2 (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 extra-nuclear 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. [less ▲]

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See detailCombined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms
Gérard, Céline ULg; Mestdagt, Mélanie; Tskitishvili, Ekaterine ULg et al

in Oncotarget (2015)

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 93 (9 ULg)