An integrative analysis reveals the mechanism of plastic stabilizers inducing breast cancer

TL;DR

This study shows that plastic stabilizers may promote breast cancer by activating specific genes linked to tumor progression.

Contribution

The study introduces a novel integrative approach combining network toxicology and biological validation to assess the carcinogenic risks of plastic stabilizers.

Findings

Plastic stabilizers bind to and activate core genes like MAPK14, PIM1, and TRDMT1 in breast cancer cells.

High expression of these genes correlates with poor prognosis in breast cancer patients.

Exposure to plastic stabilizers increases cancer cell proliferation and migration in vitro.

Abstract

Plastic stabilizers (PSs) are chemical additives that are widely used to inhibit the degradation of plastics. However, their safety concerns and potential carcinogenic risks remain unclear. This study employed network toxicology strategies to elucidate the potential toxic effects and underlying molecular mechanisms of representative PSs, including 2,6-di-tert-butylphenol (2,6-DTB), tert-butylhydroquinone (TBHQ), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328) in breast cancer (BC). Herein, we identified 69 potential genes related to PSs exposure and BC, and optimized five core targets: GSK3B, MAPK14, PARP1, PIM1, and TRDMT1, through subsequent LASSO and SVM algorithms. Based on these core genes, we constructed risk score and nomogram models, both of which revealed that high expression of these five core genes predicts poor prognosis in BC patients. Additionally, molecular docking and dynamic simulations indicated high-affinity interactions between PSs and these core targets (binding energies < -5 kcal/mol). Further correlation analysis with prediction analysis of microarray 50 (PAM50) revealed increased expression of all core genes in the basal-like subtype, especially PIM1 and TRDMT1, which also exhibited the highest risk scores. In vitro, PSs transcriptionally upregulated MAPK14, PIM1, and TRDMT1, with STAT3 mediating their transcription. Importantly, cell counting kit-8 and wound healing assays demonstrated that PSs promote BC cell proliferation and migration. Our research re-evaluates the carcinogenic risks of plastic stabilizers and suggests that PSs may enhance breast cancer progression via targets such as MAPK14, PIM1, and TRDMT1. This study introduces a new approach for evaluating the safety of plastic additives and offers novel insights into the toxicological effects of PSs.

Plastic stabilizers are ubiquitous chemical additives used to prevent plastic degradation, yet their potential role in cancer development has been largely overlooked. This study integrates computational network toxicology with biological validation to examine the carcinogenic risks of three common stabilizers: 2,6-DTB, TBHQ, and UV-328. We discovered that these chemicals specifically target and activate core genes—including MAPK14, PIM1, and TRDMT1—associated with breast cancer. Our experiments demonstrate that these stabilizers bind directly to these molecular targets, thereby driving cancer cell proliferation and migration. Furthermore, clinical analysis indicates that elevated levels of these genes correlate with poorer survival outcomes in breast cancer patients. These findings provide evidence that plastic stabilizers are not merely inert additives but potential environmental drivers of tumor progression. By elucidating the molecular mechanism linking plastic additives to cancer aggression, this research offers a scientific basis for re-evaluating the safety of these chemicals and underscores the urgent need for stricter risk assessment of plastic-associated compounds.

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