Lira María Cecilia, Rosa Francisco D, Bernacchia Juliana Lourdes, Palma Alejandra G, Paladino Natalia, Costas Mónica A, Rubio María Fernanda
Institute of Medical Research Alfredo Lanari, School of Medicine, University of Buenos Aires, Argentina; Laboratory of Molecular Biology and Apoptosis, Institute of Medical Research, University of Buenos Aires, National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires 1427, Argentina.
Laboratory of Chronobiology, National University of Quilmes, Quilmes, Buenos Aires 1876, Argentina.
Biochim Biophys Acta Mol Basis Dis. 2025 Oct;1871(7):167931. doi: 10.1016/j.bbadis.2025.167931. Epub 2025 May 28.
In breast cancer, adipocytes are the predominant cell type in the microenvironment, and the continuous communication between these tissues alters the adipose phenotype. However, molecular mechanisms promoting these changes are still poorly understood. Previously, we demonstrated that NCoA3 expression is increased in adipose tissue adjacent to breast cancer and that this increase is associated with an inflammatory profile. This study aimed to investigate the mechanisms underlying NCoA3 expression in adipocytes within the breast tumor microenvironment. We demonstrated that breast cancer-secreted TNF increases NCoA3 expression in adipocytes, and this upregulation is dependent on NF-κB transcriptional activity. Furthermore, the use of a TNF blocker prevented both coactivator overexpression and macrophages recruitment, mimicking the effects observed when NCoA3 expression was downregulated using a short hairpin RNA. These findings shed light on the molecular mechanisms by which breast cancer cells modulate adipocyte behavior, identifying NCoA3 as a key mediator in the tumor-adipose tissue crosstalk. Targeting this pathway through TNF inhibition offers promising therapeutic strategy to attenuate tumor-associated inflammation and potentially improve outcomes in breast cancer patients.
在乳腺癌中，脂肪细胞是微环境中的主要细胞类型，这些组织之间的持续交流改变了脂肪细胞表型。然而，促进这些变化的分子机制仍知之甚少。此前，我们证明在乳腺癌邻近的脂肪组织中NCoA3表达增加，且这种增加与炎症特征相关。本研究旨在探究乳腺肿瘤微环境中脂肪细胞内NCoA3表达的潜在机制。我们证明乳腺癌分泌的肿瘤坏死因子（TNF）可增加脂肪细胞中NCoA3的表达，且这种上调依赖于核因子κB（NF-κB）的转录活性。此外，使用TNF阻滞剂可防止共激活因子过表达和巨噬细胞募集，这与使用短发夹RNA下调NCoA3表达时观察到的效果相似。这些发现揭示了乳腺癌细胞调节脂肪细胞行为的分子机制，确定NCoA3是肿瘤与脂肪组织相互作用中的关键介质。通过抑制TNF靶向该途径为减轻肿瘤相关炎症并潜在改善乳腺癌患者的预后提供了有前景的治疗策略。
