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

Chanaëlle Fébrissy, Marine Adlanmerini, Christel Péqueux, Frédéric Boudou, Mélissa Buscato, Adrien Gargaros, Silveric Gilardi-Bresson, Khrystyna Boriak, Henrik Laurell, Coralie Fontaine, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Julie Guillermet-Guibert, Jean François Arnal, Raphaël Metivier, Françoise Lenfant

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)249-264
Number of pages16
JournalTheranostics
Volume14
Issue number1
DOIs
StatePublished - 2024

Keywords

  • Angiogenesis
  • Endothelial cells
  • Estrogen Receptor ERα
  • Tamoxifen
  • Tumor growth

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
  • Medicine (miscellaneous)

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