Polychlorinated biphenyls (PCBs) are a group of synthetic organic chemicals extensively used in industrial applications due to their chemical stability and insulating properties (Zarerad et al., 2023). Although many countries have banned PCBs, their persistence in the environment means they continue to be detected in various ecosystems (Liu et al., 2020). Recent studies show that PCBs remain a significant concern due to their long-lasting presence in the environment, particularly in sediments, water bodies, and wildlife, despite regulatory bans (Beyer and Biziuk, 2009). The environmental impact of PCBs is profound, as they not only accumulate in the food chain but also disrupt local ecosystems, affecting biodiversity and ecological balance. This environmental persistence poses significant health risks. Epidemiological studies and experimental data have demonstrated a link between PCBs exposure and an increased risk of several cancers, including breast cancer (Pourhassan et al., 2022; Zani et al., 2013). This association is largely attributed to PCBs’ endocrine-disrupting properties, which can interfere with hormonal regulation and contribute to carcinogenesis (Chen et al., 2015). Additionally, ongoing exposure to PCBs continues to occur through contaminated food sources (e.g., fish and dairy), occupational settings, and legacy contamination in urban areas and older buildings (Ritter et al., 2002; Osemwengie and Morgan, 2019; Malisch and Kotz, 2014). Understanding the environmental pathways through which PCBs enter and affect human health is crucial for developing effective mitigation strategies. Investigating the molecular mechanisms through which PCBs influence breast cancer progression is crucial for understanding their carcinogenic potential and for developing targeted interventions to mitigate their impact.

Breast cancer, one of the predominant neoplasms affecting women worldwide, is shaped by a multifaceted interaction of environmental exposures, lifestyle choices, and genetic predispositions (Ba et al., 2020). The escalating prevalence of breast cancer has been partially linked to environmental determinants, with prolonged exposure to chemical agents, such as PCBs, being scrutinized for their potential contributory effects (Parada et al., 2016). Despite the regulatory bans, exposure to PCBs is still prevalent, and the toxicity of these pollutants continues to affect public health, particularly in regions with legacy contamination or in populations with higher levels of exposure due to diet or occupation. Distinct functional PCB congeners exhibit varying correlations with prognostic biomarkers of breast carcinoma, as well as with the classification stages of tumors (Qiu et al., 2020). Furthermore, PCBs may elevate the risk of short-term breast cancer-specific mortality and long-term all-cause mortality in breast cancer patients (Parada et al., 2020). Previous research has demonstrated that PCBs can disrupt hormone regulation and activate cancer-related signaling pathways (Guo et al., 2020; Qin et al., 2021). Recent studies have highlighted that five specific PCB congeners (PCB 99, PCB 105, PCB 118, PCB 138, and PCB 183) are associated with an increased risk of breast cancer, establishing them as critical subjects for investigation (Liu et al., 2023). However, the evidence linking these PCBs to breast cancer remains limited and sometimes contradictory, and epidemiological studies on this topic have produced varying results. In addition, a recent meta-analysis suggests that PCB 99, PCB 183, and PCB 187 specifically elevate the risk of developing breast cancer (Leng et al., 2016). These congeners were selected for our study due to their documented presence in environmental samples and their potential association with breast cancer, as indicated by a few studies. However, the specific molecular mechanisms and pathways modulated by these PCBs in the context of breast cancer remain poorly understood and need further investigation. Studies have predominantly focused on general toxicological effects, with insufficient emphasis on comprehensive molecular interaction networks and pathways at a systems biology level. Additionally, data on the binding affinities and specific interactions of PCBs congeners with key protein targets in breast cancer are sparse. This gap necessitates a more integrative and detailed analysis to elucidate the intricate molecular interplay induced by PCBs exposure.

Understanding how PCBs influence breast cancer at the molecular level is critical for several reasons. First, it provides deeper insights into the carcinogenic mechanisms of persistent environmental pollutants. Second, it helps identify potential biomarkers for early detection and risk assessment of breast cancer related to PCBs exposure. Lastly, it contributes to the development of targeted therapies and preventive strategies. Given the ongoing exposure to PCBs through various environmental and occupational sources, addressing these knowledge gaps remains of paramount importance for public health. This research seeks to clarify the molecular mechanisms by employing network toxicology and molecular docking approaches. The focus is on examining the interactions between PCBs and key proteins that play a significant role in the progression of breast cancer.

Network toxicology represents an integrative discipline that synthesizes chemical informatics, systems biology, and bioinformatics, providing a robust framework for elucidating the mechanisms by which chemical agents can perturb biological molecular networks and compromise cellular homeostasis (Del Giudice et al., 2024). Molecular docking facilitates the simulation of complex chemical-protein interactions at the molecular level, thereby revealing potential mechanistic pathways through which these chemicals may influence the pathogenesis of cancer (Abd El-Meguid et al., 2022). Through the integration of these methodologies, this research aims to elucidate the molecular mechanisms by which chronic exposure to PCBs may modulate the initiation and progression of breast carcinoma. These findings offer a detailed molecular insight into the potential mutagenic, genotoxic, and carcinogenic effects of PCBs, linking identified targets to well-established toxicological endpoints such as DNA damage, genomic instability, and cellular transformation, which are critical in carcinogenesis. Figure 11 provides an overview of the research process. Our findings offer comprehensive insights into the molecular mechanisms by which PCBs promote breast cancer progression. By identifying key targets and pathways, this study provides potential biomarkers for breast cancer detection and highlights therapeutic intervention points. These findings are consistent with previous epidemiological and experimental evidence linking PCBs exposure to mutagenic and carcinogenic outcomes, as alterations in key signaling pathways such as PI3K-Akt and MAPK are recognized hallmarks of cancer progression (Parada et al., 2020; Wang D. et al., 2024). Understanding these mechanisms underscores the importance of addressing environmental pollutants in cancer research and aids in the formulation of public health policies to mitigate PCB exposure risks.

The strength of our study lies in the integration of network toxicology and molecular docking to systematically map PCB-induced perturbations in breast cancer-associated pathways. By combining differential expression analysis, enrichment analysis, and molecular docking, we identified several key toxicological targets and signaling pathways altered by PCBs in breast cancer, notably the PI3K-Akt and MAPK pathways, highlighting their essential roles in the disease’s pathology. These pathways are known to be involved in both genotoxicity and carcinogenicity, and their dysregulation by environmental pollutants like PCBs has been documented in several studies (Li et al., 2022; An et al., 2014; Radice et al., 2008; Song and Freedman, 2005). The PI3K-Akt pathway’s interaction with EZH2 and EGF is critical in this context. EZH2, as an epigenetic regulator, directly influences PI3K-Akt signaling by repressing tumor suppressor genes like PTEN (a key regulator of PI3K-Akt), thereby amplifying AKT1 activation and downstream survival signals (Yang et al., 2020; Wang J. et al., 2024). Similarly, EGF, via its receptor EGFR, activates both PI3K-Akt and MAPK pathways through phosphorylation cascades (Lv et al., 2015; Hwang et al., 2011). PCBs’ binding to EGF, as observed in our docking results, may stabilize EGFR-EGF interactions, prolonging MAPK/ERK and PI3K-Akt signaling, which drives proliferation and metabolic adaptation in tumor cells. This interaction aligns with the known mutagenic effects of PCBs, where persistent activation of growth signaling pathways can lead to DNA damage, mutation, and cellular transformation (Mutlu et al., 2016).

The PI3K-Akt pathway, known for its involvement in regulating cell survival, proliferation, and metabolism, is frequently dysregulated in breast cancer (Miricescu et al., 2020; Zhu et al., 2022; Sharma et al., 2017). Increased activation of this pathway, observed in our study through elevated AKT1 and BRCA1 expression, can lead to enhanced tumor cell survival and resistance to apoptosis (Foster et al., 2009; Wang et al., 2016). This dysregulation may serve as a potential target for preventive intervention, particularly given EZH2’s role in sustaining PI3K-Akt hyperactivity through epigenetic silencing of PTEN, as noted above. Such dysregulation of the PI3K-Akt pathway is a key contributor to PCB-induced carcinogenesis, as it has been shown in both animal and human studies that PCB exposure can lead to the genomic instability that fuels cancer progression (Ali et al., 2016; Qin et al., 2022). This aligns with previous research indicating that aberrant PI3K-Akt signaling contributes to aggressive breast cancer phenotypes and poor patient outcomes (Cancer Genome Atlas Network, 2012; Tian et al., 2021; Guo et al., 2023). In addition to the PI3K-Akt pathway, our study also highlights the significance of the MAPK signaling pathway in PCBs-induced breast cancer. The role of the MAPK pathway in cancer-related genotoxicity has been widely documented, with studies showing that PCBs exposure can promote mutagenic events through MAPK-driven proliferation and invasion (Zingales et al., 2021). This mechanistic link explains how PCB-EGF interactions could directly amplify oncogenic MAPK signalling, corroborating our observed disregulation of proliferation-associated genes. The MAPK pathway, which regulates cellular responses to growth signals and stress, also plays a significant role in cancer progression (Park and Baek, 2022; Santarpia et al., 2012). Our findings highlight that PCBs exposure leads to alterations in MAPK pathway components, such as AKT1 and EGF. Dysregulation of MAPK signaling has been associated with increased cell proliferation and metastatic potential in breast cancer (Wang et al., 2023; Wu et al., 2023). The upregulation of EGF, a key growth factor in this pathway, suggests that PCBs may promote tumor growth and progression by enhancing EGF receptor signaling, a mechanism previously linked to poor prognosis in breast cancer (Balanis and Carlin, 2017; Garcia et al., 2006). This underscores the interconnected roles of EZH2 and EGF in PCB-mediated pathway dysregulation: EZH2 epigenetically reinforces PI3K-Akt activation, while EGF-EGFR-PCB complexes drive parallel MAPK signaling, creating a synergistic oncogenic network. This dual pathway activation reinforces the carcinogenic potential of PCBs, as evidenced by their ability to induce genomic instability and mutagenic damage in breast cancer cells.

The recognition of EZH2, EGF, and AKT1 as pivotal toxicological targets in PCBs-mediated breast carcinogenesis provides critical insights into the molecular pathways through which PCBs facilitate tumor progression. EZH2, a histone methyltransferase and key epigenetic regulator, has been extensively linked to cancer progression through its role in transcriptional repression of tumor suppressor genes and promotion of cancer stem cell-like properties (Kim and Roberts, 2016). Overexpression of EZH2 is associated with poor prognosis in breast cancer (Pietersen et al., 2008). The involvement of EZH2 in PCB-induced carcinogenesis is supported by previous studies demonstrating that exposure to persistent environmental pollutants like PCBs can lead to epigenetic modifications, contributing to cancer risk (Singh, 2024). Our molecular docking analysis, which demonstrated strong binding between PCBs and EZH2, hypothesizes that PCBs exposure could potentially influence EZH2’s oncogenic activity, possibly leading to epigenetic modifications that promote tumor growth and therapy resistance. This aligns with epidemiological studies indicating that individuals exposed to high PCB levels have increased risks of developing cancers with epigenetic alterations (Guo et al., 2024). Targeting EZH2 may represent a potential preventive strategy for high-risk populations exposed to PCBs, offering a molecular approach to mitigate pollutant-induced epigenetic alterations. EGF is a well-known growth factor that drives tumor cell proliferation and survival through its activation of the EGFR signaling pathway (Feng et al., 2012; Lee et al., 2021). Similarly, the strong interaction between PCBs and EGF underscores the significance of EGF in breast cancer pathology.

However, it is important to acknowledge the limitations of our study. While the molecular docking results and pathway analysis provide valuable insights into the potential mechanisms by which PCBs influence breast cancer progression, we cannot draw definitive conclusions about the clinical applicability of these findings. The relationship between PCBs exposure and breast cancer is based on epidemiological data, and it remains challenging to identify individual patients whose breast cancer may be directly attributed to PCBs exposure. Further clinical and molecular studies are needed to validate the toxicological relevance of these findings in the context of human breast cancer. Thus, while the targets identified in our study are relevant for understanding the biological mechanisms involved, further research, including clinical validation, is required before these findings can inform therapeutic strategies. Functional assays, such as gene knockdown experiments, would be necessary to confirm the mechanisms suggested in this study and provide direct evidence of the molecular interactions proposed. Additionally, rather than speculating about individualized therapies, future studies should aim to better characterize the epidemiological and molecular associations between PCBs exposure and breast cancer. It is also crucial to explore the combined effects of PCBs exposure with other environmental pollutants, including metals, dioxins, and chlorinated pesticides, which may synergize to exacerbate carcinogenic outcomes. One potential direction is to explore the role of environmental pollutants in contributing to cancer-related health disparities and whether certain populations are more vulnerable to PCBs-induced carcinogenesis. Considering the environmental and biological complexities of PCBs exposure, especially as a mixture of chemicals, further studies should address how cumulative exposure and interactions with other pollutants affect breast cancer risk. Further research into the molecular signatures of PCBs-exposed tumors may also provide opportunities to develop broader preventive strategies targeting the identified pathways, including the PI3K-Akt and MAPK signaling pathways. These findings could contribute to public health measures aimed at reducing PCBs exposure and preventing breast cancer.

In conclusion, our study underscores the importance of addressing environmental pollutants such as PCBs in cancer research. By identifying key molecular targets and pathways involved in PCB-induced breast cancer, we provide a foundation for future studies aimed at developing targeted therapies and preventive measures. The integration of network toxicology and molecular docking represents a powerful approach to elucidate the complex molecular interactions underlying environmental pollutant-induced cancers, and our findings highlight the potential of this approach to uncover novel therapeutic intervention points.