Wang Zhen, Cao Meng, Gao Tian, Xu Xinyue, Yu Weihua, Liu Jiangzheng, Liu Rui, Zhang Xiaodi, Li Fei, Hai Chunxu
Department of Military Toxicology and Chemoprevention Medicine, Department of Military Preventive Medicine, The Fourth Military Medical University, Xi'an City, Shaanxi Province, China.
Department of Military Toxicology and Chemoprevention Medicine, Department of Military Preventive Medicine, The Fourth Military Medical University, Xi'an City, Shaanxi Province, China; Third Affiliated Hospital of Air Force Medical University, Xi'an City, Shaanxi Province, China.
Toxicology. 2025 Jun;514:154123. doi: 10.1016/j.tox.2025.154123. Epub 2025 Mar 23.
Breast cancer (BC) is one of the most common types of cancer and is caused by the complex interplay of genetic and environmental factors, such as an unhealthy lifestyle, family history of illness, reproductive factors, and ageing. However, increasing evidence has revealed that manufactured organic pollutants such as bisphenols are closely related to BC. Bisphenols exposure can promote the progression of BC through multiple complicated and variable molecular mechanisms. Reanalysis of existing data on this topic may reveal molecular markers with clinical value. In this study, we identified four key genes [keratin 14 (KRT14), keratin 5 (KRT5), acyl-CoA synthetase long chain family member 1 (ACSL1) and matrix metallopeptidase 1 (MMP1)] related to both bisphenols exposure and BC by employing the Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas Cervical Cancer (TCGA-CESC) dataset; notably, KRT14 expression exhibited the most significant difference between tumour and normal tissues. Further analysis of the functions and biological processes associated with KRT14 and related regulatory molecules revealed that bisphenols exposure induces BC-promoting characteristics and aggressive behaviour-related signaling pathways, such as the steroid biosynthesis, Forkhead box (FOXO) and prolactin signaling pathways. To confirm the expression and biological effects of KRT14, we conducted relevant experiments. In vitro studies revealed that bisphenols such as bisphenol A (BPA) exposure significantly affected the proliferation, migration, and invasion of MCF-7 cells by inhibiting KRT14 expression. Similarly, we also observed a decrease in KRT14 expression in BPA induced abnormal breast tissue in mice. In summary, our study revealed potential genes and pathways associated with bisphenols exposure in BC.
乳腺癌（BC）是最常见的癌症类型之一，由遗传和环境因素的复杂相互作用引起，如不健康的生活方式、家族病史、生殖因素和衰老。然而，越来越多的证据表明，双酚等人工合成有机污染物与乳腺癌密切相关。双酚暴露可通过多种复杂多变的分子机制促进乳腺癌的进展。对该主题现有数据的重新分析可能会揭示具有临床价值的分子标记。在本研究中，我们通过使用比较毒理基因组学数据库（CTD）和癌症基因组图谱宫颈癌（TCGA-CESC）数据集，确定了四个与双酚暴露和乳腺癌相关的关键基因[角蛋白14（KRT14）、角蛋白5（KRT5）、酰基辅酶A合成酶长链家族成员1（ACSL1）和基质金属肽酶1（MMP1）]；值得注意的是，KRT14在肿瘤组织和正常组织之间的表达差异最为显著。对与KRT14和相关调节分子相关的功能和生物学过程的进一步分析表明，双酚暴露诱导了促进乳腺癌的特征和与侵袭性行为相关的信号通路，如类固醇生物合成、叉头框（FOXO）和催乳素信号通路。为了证实KRT14的表达和生物学效应，我们进行了相关实验。体外研究表明，双酚A（BPA）等双酚暴露通过抑制KRT14表达显著影响MCF-7细胞的增殖、迁移和侵袭。同样，我们还观察到在BPA诱导的小鼠异常乳腺组织中KRT14表达降低。总之，我们的研究揭示了与乳腺癌中双酚暴露相关的潜在基因和通路。
