Li Jiajun, Wang Deqi, Song Sihan, Wang Yi, Wu Xinlei, Du Zhuoyi, Hong Yanggang
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
Funct Integr Genomics. 2025 Jun 4;25(1):119. doi: 10.1007/s10142-025-01616-y.
Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are persistent environmental contaminants linked to adverse health effects, including an increased risk of breast cancer. However, the molecular mechanisms through which PFAS contribute to breast cancer development remain poorly understood. In this study, we employed an integrated approach combining network toxicology, single-cell sequencing, spatial transcriptomics, and molecular simulation to investigate the effects of PFAS on breast cancer. By constructing a protein-protein interaction (PPI) network, we identified six core genes (PPARG, CD36, FABP4, PPARGC1A, LPL, and PCK1) that play a significant role in the development of breast cancer. These genes are involved in key cellular processes such as lipid metabolism, oxidative phosphorylation, and immune regulation, all of which are disrupted by PFAS exposure. Single-cell and spatial transcriptomic analyses revealed that these genes are predominantly expressed in endothelial, myeloid, and cancer-associated fibroblasts within the tumor microenvironment. Molecular simulation further confirmed strong binding energies between PFAS and these target proteins, suggesting direct interactions. Our findings provide novel insights into how PFAS may promote breast cancer progression at the molecular level and highlight the need for further research on environmental pollutants in cancer risk assessment and public health initiatives.
全氟和多氟烷基物质（PFAS），特别是全氟辛酸（PFOA）和全氟辛烷磺酸（PFOS），是持久性环境污染物，与不良健康影响相关，包括乳腺癌风险增加。然而，PFAS促成乳腺癌发展的分子机制仍知之甚少。在本研究中，我们采用了一种综合方法，结合网络毒理学、单细胞测序、空间转录组学和分子模拟来研究PFAS对乳腺癌的影响。通过构建蛋白质-蛋白质相互作用（PPI）网络，我们确定了六个核心基因（PPARG、CD36、FABP4、PPARGC1A、LPL和PCK1），它们在乳腺癌发展中起重要作用。这些基因参与关键的细胞过程，如脂质代谢、氧化磷酸化和免疫调节，而所有这些过程都会因PFAS暴露而受到干扰。单细胞和空间转录组分析表明，这些基因主要在肿瘤微环境中的内皮细胞、髓样细胞和癌症相关成纤维细胞中表达。分子模拟进一步证实了PFAS与这些靶蛋白之间有很强的结合能，表明存在直接相互作用。我们的研究结果为PFAS如何在分子水平上促进乳腺癌进展提供了新的见解，并强调在癌症风险评估和公共卫生倡议中需要对环境污染物进行进一步研究。
