References of "Pequeux, Christel"
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See detailWhole blood microsampling for the quantitation of estetrol without derivatization by liquid chromatography-tandem mass spectrometry
Nys, Gwenaël ULg; Gallez, Anne ULg; Kok, Miranda ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2017), 140

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See detailCancer associated fibroblast-derived integrin α11 regulates PDGFRβ signaling to promote breast cancer progression
Primac, Irina ULg; Blacher, Silvia ULg; cimino, Jonathan et al

Conference (2017, April 24)

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by ... [more ▼]

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by mesenchymal cells and is correlated with fibroblast activation and matrix reorganization. While the role of ITGA11 in wound healing has been well described, only a very limited number of reports have assessed its role in the cancer disease. This research project aims to investigate the role of stromal ITGA11 in breast cancer. To analyze the in vivo effects of ITGA11 on tumor insurgence, growth and metastasis, we crossed the oncogenic MMTv-PyMT mice with the ITGA11 KO/WT mice, which develop spontaneously breast tumors. ITGA11 deletion strongly delayed tumor growth and metastasis in PyMT mouse model. ITGA11 was poorly expressed at early stages of the tumor progression and its expression was strongly increased in the late stage invasive carcinomas. Importantly, a reduced angiogenesis and collagen content was observed in tumors lacking of ITGA11. Furthermore, a strong co-localization between ITGA11 and PDGFRb, but not other CAF markers such as alpha smooth actin, was also observed within the tumor stroma, suggesting that ITGA11 defines a subpopulation of CAFs, which is not represented by myofibroblasts, but rather PDGFRb+ CAFs. For mechanistic investigation, CAFs and breast cancer cells were isolated from the PyMT model. ITGA11 co-immunoprecipitated with PDGFRb in the isolated CAFs and regulated its phosphorylation. Interestingly, ITGA11-deficient CAFs failed to promote CAF and cancer cell invasion, in contrast to WT CAFs in a spheroid invasion assay. A high throughput comparative proteomics analysis on CAF spheroids in 3D a system was next performed. Proteomics data identified several proteins with relevance in the cancer disease which were significantly modulated in CAFs through ITGA11 down-regulation. The top-ranking candidates are under validation and molecular pathways, which may link these targets and ITGA11 will be further analyzed in the in vitro models. Overall, these in vivo and in vitro data show that ITGA11 defines a PDGFRβ+ subpopulation of CAFs distinct from α-SMA+ myofibroblasts that promote tumor cell invasion and angiogenesis at late stages of carcinoma evolution. ITGA11 is a promising target within the stroma of breast cancer and further investigations of its molecular signaling pathways will be of great relevance. [less ▲]

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See detailDose-dependent effect of Estetrol on Angiogenesis and Tumor Growth
Gallez, Anne ULg; Blacher, Silvia ULg; Lenfant, Françoise et al

Poster (2017, April 24)

Hormone replacement therapies (HRT) based on estrogen preparations are the most powerful treatments to prevent menopause symptoms. However, they are associated to an increased risk of breast cancer and ... [more ▼]

Hormone replacement therapies (HRT) based on estrogen preparations are the most powerful treatments to prevent menopause symptoms. However, they are associated to an increased risk of breast cancer and they sustain the development of Estrogen Receptor α-positive tumors (ERα+). In addition, we have previously observed that estradiol (E2) can promote the growth of ERα-negative (ERα-) tumors, by increasing tumor angiogenesis that subsequently improves oxygen and nutrients delivery, thereby preventing hypoxia and necrosis. To identify new and safe drugs for the development of HRT presenting a better benefit/risk ratio, it is therefore necessary to evaluate the potential impact of new candidates on both ERα+ and ERα- tumors. In this context, estetrol (E4), a natural estrogen exclusively produced by the fetal liver, is a promising candidate. [less ▲]

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See detailLc-chip versus UHPLC-tandem mass spectrometry for the quantitation of estetrol and estradiol without derivatization after whole blood microsampling
Nys, Gwenaël ULg; Servais, Anne-Catherine ULg; Pequeux, Christel ULg et al

Conference (2017, March 29)

the aim of this work was to conduct a PK study on mice to select the most appropriate administration route for E2 and E4 formulations. To achieve this goal, a reference method for the quantitation of both ... [more ▼]

the aim of this work was to conduct a PK study on mice to select the most appropriate administration route for E2 and E4 formulations. To achieve this goal, a reference method for the quantitation of both estrogens after whole blood microsampling was developed and validated on a UHPLC-MS/MS system. This reference method was later transferred on LC-chip device and both methods were compared in terms of analytical parameters such as response function, accuracy, precision, trueness and limit of quantification. [less ▲]

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See detailAccurate Control of 17beta-Estradiol Long-Term Release Increases Reliability and Reproducibility of Preclinical Animal Studies.
Gérard, Céline ULg; Gallez, Anne ULg; Dubois, Charline ULg et al

in Journal of Mammary Gland Biology & Neoplasia (2017), 22(1), 1-11

Estrogens are the subject of intensive researches aiming to elucidate their mechanism of action on the various tissues they target and especially on mammary gland and breast cancer. The use of ready-to ... [more ▼]

Estrogens are the subject of intensive researches aiming to elucidate their mechanism of action on the various tissues they target and especially on mammary gland and breast cancer. The use of ready-to-use slow releasing devices to administer steroids, especially estrogens, to small experimental animals remains the method of choice in terms of animal well-being and of safety for both the researcher and the animal. In this study, we evaluated and compared, in vitro and in vivo, the release kinetic of estradiol (E2) over sixty days from two different slow-releasing systems: the matrix pellet (MP) and the reservoir implant (RI). We compared the impact of these systems in three E2-sensitive mouse models : mammary gland development, human MCF7 adenocarcinoma xenograft and mouse melanoma progression. The real amount of E2 that is released from both types of devices could differ from manufacturer specifications due to inadequate release for MP and initial burst effect for RI. Compared to MP, the interindividual variability was reduced with RI thanks to a superior control of the E2 release. Depending on the dose-dependent sensitivity of the physiological or pathological readout studied, this could lead to an improvement of the statistical power of in vivo experiments and thus to a reduction of the required animal number. Altogether, our data draw attention on the importance to adequately select the slow-releasing device that is the most appropriated to a specific experiment to better fulfill the 3Rs rule (Replacement, Reduction, Refinement) related to animal welfare and protection. [less ▲]

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See detailEstrogen receptors and estetroldependent neuroprotective actions: a pilot study
Tskitishvili, Ekaterine ULg; Pequeux, Christel ULg; Munaut, Carine ULg et al

in Journal of Endocrinology (2017), 232(1), 85-95

Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic-ischemic encephalopathy. We aimed to define the role of estrogen ... [more ▼]

Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic-ischemic encephalopathy. We aimed to define the role of estrogen receptors in E4-dependent actions in neuronal cell cultures and prove the promyelinating effect of E4. In vitro the antioxidative and cell survival/proliferating effects of E4 on H2O2-induced oxidative stress in primary hippocampal cell cultures were studied using different combinations of specific inhibitors for ERalpha (MPP dihydrochloride), ERbeta (PHTTP), GPR30 (G15) and palmytoilation (2-BR). LDH activity and cell survival assays were performed. In vivo the promyelinating role of different concentrations of E4 (1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day) was investigated using the hypoxic-ischemic brain damage model in the 7-day-old immature rats before/after the induction of hypoxic-ischemic insult. Myelin basic protein (MBP) immunostaining was performed on brain coronal sections. Our results show that LDH activity is significantly upregulated in cell cultures where the E4's effect was completely blocked by concomitant treatment either with ERalpha and ERbeta inhibitors (MPP and PHTPP, respectively), or ERalpha and ERbeta inhibitors combined with 2-BR. Cell survival is significantly downregulated in cell cultures where the effect of E4 was blocked by ERbeta inhibitor (PHTTP) alone. The blockage of GRP30 receptor did affect neither LDH activity nor cell survival. MBP immunostaining is significantly upregulated in E4-pretreated groups at a concentration of 5 mg/kg/day and 50 mg/kg/day E4, whereas the MBP-positive area OD ratio is significantly increased in all the E4-treated groups. E4's antioxidative actions mostly depend on ERalpha and ERbeta, whereas neurogenesis and possibly promyelinating activities might be realized through ERbeta. [less ▲]

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See detailPharmacokinetic study of estetrol in murin model developing a whole blood microsampling, extraction procedure and an UHPLC-MS/MS method
Nys, Gwenaël ULg; Servais, Anne-Catherine ULg; Pequeux, Christel ULg et al

Conference (2016, October 17)

We developed a sensitive UHPLC-MS/MS method with a simple yet efficient sample collection and preparation protocol to accurately quantify E4 in whole blood. This method was then successfully applied for ... [more ▼]

We developed a sensitive UHPLC-MS/MS method with a simple yet efficient sample collection and preparation protocol to accurately quantify E4 in whole blood. This method was then successfully applied for the pharmacokinetic study of E4 in a murin model providing the best administration route for E4. The innovative sampling allowed decreasing the number of animals used for the study as VAMS only draws few microliters of blood thus leaving the mice alive for the whole PK study reducing the inter-individual variability. [less ▲]

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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 ▲]

Detailed reference viewed: 38 (11 ULg)
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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 ▲]

Detailed reference viewed: 39 (1 ULg)