Theranostics 2024; 14(1):249-264. doi:10.7150/thno.87306 This issue Cite

Research Paper

Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth

Chanaëlle Fébrissy1, Marine Adlanmerini1, Christel Péqueux2, Frédéric Boudou1, Mélissa Buscato1, Adrien Gargaros1, Silveric Gilardi-Bresson1, Khrystyna Boriak1, Henrik Laurell1, Coralie Fontaine1, Benita S. Katzenellenbogen3, John A. Katzenellenbogen3, Julie Guillermet-Guibert4, Jean-François Arnal1, Raphaël Metivier5, Françoise Lenfant1✉

1. INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France.
2. Laboratoire de Biologie des Tumeurs et du Développement, GIGA-Cancer, Université de Liège, B23, Liège, Belgium.
3. Departments of Molecular and Integrative Physiology and Chemistry, University of Illinois, Urbana, Illinois, USA.
4. INSERM U1037, CRCT, Oncopole- 31 037 Toulouse cedex, France.
5. Institut de Génétique De Rennes (IGDR). UMR 6290 CNRS-Université de Rennes, ERL INSERM U1305. CS 74205- 35042 Rennes Cedex, France.

Citation:
Fébrissy C, Adlanmerini M, Péqueux C, Boudou F, Buscato M, Gargaros A, Gilardi-Bresson S, Boriak K, Laurell H, Fontaine C, Katzenellenbogen BS, Katzenellenbogen JA, Guillermet-Guibert J, Arnal JF, Metivier R, Lenfant F. Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth. Theranostics 2024; 14(1):249-264. doi:10.7150/thno.87306. https://www.thno.org/v14p0249.htm
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Abstract

Graphic abstract

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.

Keywords: Tamoxifen, Angiogenesis, Estrogen Receptor ERα, Endothelial cells, Tumor growth


Citation styles

APA
Fébrissy, C., Adlanmerini, M., Péqueux, C., Boudou, F., Buscato, M., Gargaros, A., Gilardi-Bresson, S., Boriak, K., Laurell, H., Fontaine, C., Katzenellenbogen, B.S., Katzenellenbogen, J.A., Guillermet-Guibert, J., Arnal, J.F., Metivier, R., Lenfant, F. (2024). Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth. Theranostics, 14(1), 249-264. https://doi.org/10.7150/thno.87306.

ACS
Fébrissy, C.; Adlanmerini, M.; Péqueux, C.; Boudou, F.; Buscato, M.; Gargaros, A.; Gilardi-Bresson, S.; Boriak, K.; Laurell, H.; Fontaine, C.; Katzenellenbogen, B.S.; Katzenellenbogen, J.A.; Guillermet-Guibert, J.; Arnal, J.F.; Metivier, R.; Lenfant, F. Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth. Theranostics 2024, 14 (1), 249-264. DOI: 10.7150/thno.87306.

NLM
Fébrissy C, Adlanmerini M, Péqueux C, Boudou F, Buscato M, Gargaros A, Gilardi-Bresson S, Boriak K, Laurell H, Fontaine C, Katzenellenbogen BS, Katzenellenbogen JA, Guillermet-Guibert J, Arnal JF, Metivier R, Lenfant F. Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth. Theranostics 2024; 14(1):249-264. doi:10.7150/thno.87306. https://www.thno.org/v14p0249.htm

CSE
Fébrissy C, Adlanmerini M, Péqueux C, Boudou F, Buscato M, Gargaros A, Gilardi-Bresson S, Boriak K, Laurell H, Fontaine C, Katzenellenbogen BS, Katzenellenbogen JA, Guillermet-Guibert J, Arnal JF, Metivier R, Lenfant F. 2024. Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth. Theranostics. 14(1):249-264.

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