INSERM U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, BP 84225, 31 432 Toulouse cedex 04, France.
Laboratoire de Biologie des Tumeurs et du Développement, GIGA-Cancer, Université de Liège, B23, Liège, Belgium.
Theranostics. 2024 Jan 1;14(1):249-264. doi: 10.7150/thno.87306. eCollection 2024.
: 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. 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. 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 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. 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.
17β-雌二醇（E2）可以通过肿瘤微环境中内皮 ERα 的激活，直接促进 ERα 阴性癌细胞的生长，从而增加正常化的肿瘤血管生成。ERα 通过其核转录 AF-1 和 AF-2 反式激活功能作为转录因子发挥作用，但膜 ERα 在血管内皮中也发挥着重要作用。本研究旨在阐明这两条途径在 ERα 阴性肿瘤生长中的各自作用。此外，我们还描述了他莫昔芬（一种选择性雌激素受体调节剂（SERM））在 ERα 阴性肿瘤生长和血管生成中的作用，因为我们最近证明他莫昔芬通过对 ERα 活性的复杂调节来影响血管功能。将 ERα 阴性 B16K1 癌细胞移植到 ERα 亚功能突变的免疫功能正常的小鼠中，并在这些不同模型中分析了它们对 E2 和/或他莫昔芬治疗的反应。此外，还分析了内皮细胞对这些不同处理的 RNA 测序，并通过 RT-qPCR 和 Western blot 进行了验证。我们证明，核和膜 ERα 的作用都需要 E2 的促肿瘤作用，而他莫昔芬通过抑制血管生成但促进血管正常化，完全阻断了 E2 诱导的肿瘤生长。RNA 测序表明，他莫昔芬抑制了 E2 诱导的基因，但也启动了一个特定的转录程序，该程序特别调节了血管生成基因，并在血管内皮细胞中差异调节了糖酵解、氧化磷酸化和炎症反应。这些发现为他莫昔芬通过调节一些转录因子来特异性抑制血管生成提供了证据，这可能为管理影响 ERα 阴性肿瘤肿瘤微环境的癌症治疗策略开辟了新的前景。
