Institute of Medical Research Alfredo Lanari, School of Medicine, University of Buenos Aires, Ciudad Autónoma de Buenos Aires 1427, Argentina.
Laboratory of Chronobiology, National University of Quilmes, Quilmes, Buenos Aires 1876, Argentina.
Oncol Rep. 2023 May;49(5). doi: 10.3892/or.2023.8542. Epub 2023 Apr 7.
Nuclear receptor coactivator 3 (NCoA3) is a transcriptional coactivator of NF‑κB and other factors, which is expressed at relatively low levels in normal cells and is amplified or overexpressed in several types of cancer, including breast tumors. NCoA3 levels have been shown to be decreased during adipogenesis; however, its role in tumor‑surrounding adipose tissue (AT) remains unknown. Therefore, the present study assessed the modulation of NCoA3 in breast cancer‑associated adipocytes and evaluated its association with the expression of inflammatory markers. 3T3‑L1 adipocytes were stimulated with conditioned medium from human breast cancer cell lines and the expression levels of NCoA3 were evaluated by reverse transcription‑quantitative (q)PCR. NF‑κB activation was measured by immunofluorescence, and tumor necrosis factor and monocyte chemoattractant protein 1 levels were analyzed by qPCR and dot blot assays. The results obtained from the model were supported using mammary AT (MAT) from female mice, MAT adjacent to tumors from patients with breast cancer and bioinformatics analysis. The results revealed that adipocytes expressing high levels of NCoA3 were mainly associated with a pro‑inflammatory profile. In 3T3‑L1 adipocytes, NCoA3 downregulation or NF‑κB inhibition reversed the expression of inflammatory molecules. In addition, MAT from patients with a worse prognosis exhibited high levels of this coactivator. Notably, adipocyte NCoA3 levels could be modulated by inflammatory signals from tumors. The modulation of NCoA3 levels in synergy with NF‑κB activity in MAT in a tumor context could be factors required to establish breast cancer‑associated inflammation. As adipocytes are involved in the development and progression of breast cancer, this signaling network deserves to be further investigated to improve future tumor treatments.
核受体共激活因子 3(NCoA3)是 NF-κB 和其他因子的转录共激活因子,在正常细胞中表达水平较低,在包括乳腺癌在内的几种类型的癌症中被扩增或过表达。已经表明,NCoA3 的水平在脂肪生成过程中降低;然而,其在肿瘤周围脂肪组织(AT)中的作用尚不清楚。因此,本研究评估了 NCoA3 在乳腺癌相关脂肪细胞中的调节作用,并评估了其与炎症标志物表达的相关性。用来自人乳腺癌细胞系的条件培养基刺激 3T3-L1 脂肪细胞,并通过逆转录定量(q)PCR 评估 NCoA3 的表达水平。通过免疫荧光测定 NF-κB 的激活,通过 qPCR 和斑点印迹分析测定肿瘤坏死因子和单核细胞趋化蛋白 1 的水平。使用雌性小鼠的乳腺 AT(MAT)、来自乳腺癌患者的肿瘤附近的 MAT 和生物信息学分析支持从模型中获得的结果。结果表明,表达高水平 NCoA3 的脂肪细胞主要与促炎表型相关。在 3T3-L1 脂肪细胞中,NCoA3 下调或 NF-κB 抑制逆转了炎症分子的表达。此外,预后较差的患者的 MAT 表现出高水平的这种共激活因子。值得注意的是,肿瘤的炎症信号可以调节脂肪细胞的 NCoA3 水平。在肿瘤背景下,MAT 中 NCoA3 水平与 NF-κB 活性的协同调节可能是建立乳腺癌相关炎症所需的因素。由于脂肪细胞参与乳腺癌的发生和发展,这个信号网络值得进一步研究,以改善未来的肿瘤治疗。