[en] Rationale: 17β-estradiol (E2) can directly promote the growth of ERα-negative cancer cells through activation of endothelial ERα in the tumor microenvironment, thereby increasing a normalized tumor angiogenesis. ERα acts as a transcription factor through its nuclear transcriptional AF-1 and AF-2 transactivation functions, but membrane ERα plays also an important role in endothelium. The present study aims to decipher the respective roles of these two pathways in ERα-negative tumor growth. Moreover, we delineate the actions of tamoxifen, a Selective Estrogen Receptor Modulator (SERM) in ERα-negative tumors growth and angiogenesis, since we recently demonstrated that tamoxifen impacts vasculature functions through complex modulation of ERα activity. Methods: ERα-negative B16K1 cancer cells were grafted into immunocompetent mice mutated for ERα-subfunctions and tumor growths were analyzed in these different models in response to E2 and/or tamoxifen treatment. Furthermore, RNA sequencings were analyzed in endothelial cells in response to these different treatments and validated by RT-qPCR and western blot. Results: We demonstrate that both nuclear and membrane ERα actions are required for the pro-tumoral effects of E2, while tamoxifen totally abrogates the E2-induced in vivo tumor growth, through inhibition of angiogenesis but promotion of vessel normalization. RNA sequencing indicates that tamoxifen inhibits the E2-induced genes, but also initiates a specific transcriptional program that especially regulates angiogenic genes and differentially regulates glycolysis, oxidative phosphorylation and inflammatory responses in endothelial cells. Conclusion: These findings provide evidence that tamoxifen specifically inhibits angiogenesis through a reprogramming of endothelial gene expression via regulation of some transcription factors, that could open new promising strategies to manage cancer therapies affecting the tumor microenvironment of ERα-negative tumors.
Disciplines :
Oncology
Author, co-author :
Fébrissy, Chanaëlle; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Adlanmerini, Marine; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Pequeux, Christel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Boudou, Frédéric; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Buscato, Mélissa; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Gargaros, Adrien; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Gilardi-Bresson, Silveric; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Boriak, Khrystyna; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Laurell, Henrik; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Fontaine, Coralie; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Katzenellenbogen, Benita S; Departments of Molecular and Integrative Physiology and Chemistry, University of Illinois, Urbana, Illinois, USA
Katzenellenbogen, John A; Departments of Molecular and Integrative Physiology and Chemistry, University of Illinois, Urbana, Illinois, USA
Arnal, Jean-François; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
Metivier, Raphaël; Institut de Génétique De Rennes (IGDR). UMR 6290 CNRS-Université de Rennes, ERL INSERM U1305. CS 74205- 35042 Rennes Cedex, France
Lenfant, Françoise; INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France
The work at INSERM U1297 was supported by INSERM, CHU and Université de Toulouse III, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale and Region-OccitanieMP 0014573- FEDER-REGEN-EVE. C.F. was funded by ANR-18-CE14-0016/ ESTROSHEAR and Ligue Nationale contre la Cancer. Work at the CNRS UMR6290 was supported by the CNRS and the University of Rennes. Research by B.S.K. and J.A.K. was supported by National Institutes of Health/NCI grant CA220484 and grants BCRF-083 and BCRF-084 from the Breast Cancer Research Foundation.The work at INSERM U1297 was supported by INSERM, CHU and Université de Toulouse III, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale and Region-Occitanie- MP 0014573-FEDER-REGEN-EVE. C.F. was funded by ANR-18-CE14-0016/ ESTROSHEAR and Ligue Nationale contre la Cancer. Work at the CNRS UMR6290 was supported by the CNRS and the University of Rennes. Research by B.S.K. and J.A.K. was supported by National Institutes of Health/NCI grant CA220484 and grants BCRF-083 and BCRF-084 from the Breast Cancer Research Foundation.
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