Effect of pesticides on breast cancer tumor

Abstract

Breast cancer is the most common malignancy among women worldwide. Increasing evidence suggests that chronic exposure to pesticides, many of which act as endocrine-disrupting chemicals, represents a significant and underappreciated determinant for both cancer origin and progression. In this review, we reported the most recent epidemiological data, exposure pathways, and mechanistic insights linking major pesticide classes, including persistent organochlorines, organophosphates, triazines, carbamates, pyrethroids, neonicotinoids, and glyphosate-based herbicides, to breast carcinogenesis. These compounds are ubiquitous, detectable in food, water, household dust, and occupational environments, and display high lipophilicity that enables long-term bioaccumulation in adipose-rich breast tissue. Therefore, recognition of pesticides as modifiable environmental determinants of breast cancer should prompt strengthened regulation, improved biomonitoring, and public-health strategies aimed at reducing chronic exposure.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13062-025-00709-9.

Introduction

Epidemiology of breast cancer: incidence and risk factors

Breast cancer (BC) is currently the most frequent cancer in women, resulting in a major cause of death [1]. Indeed, World Health Organization (WHO) data indicate circa 670,000 deaths and 2.3 million new diagnosis every year [2, 3]. Projections suggest that by 2050, the number of new cases could rise by 38%, with a 68% increase in BC-related mortality [4]. Although BC is a global health issue, its impact is not evenly distributed across populations. High-income zones such as Australia, New Zealand, North America, and Europe report incidence rates exceeding 100 cases per 100,000 women annually [5]. These high rates reflect both enhanced diagnostic capacity, largely due to widespread mammography screening programs, and a higher prevalence of risk factors associated with Western lifestyles [5]. Both genetic and non-genetic elements play a crucial role in the development of BC, a complex and multifactorial disease [6, 7]. It is estimated that up to 10% of cases are due to inherited genetic predispositions, primarily involving well-known mutations in genes such as BRCA1 and BRCA2 [8, 9]. However, most BC cases occur sporadically and are not linked to hereditary mutations, but they exhibit specific molecular characteristics associated with prognosis and response to therapy Fig. 1. These sporadic cases are largely associated with modifiable risk factors, including lifestyle habits, such as alcohol consumption, tobacco use, and diet, as well as environmental exposures [7, 10, 11]. Given that only a small proportion of BC cases can be attributed to known genetic causes there is increasing concern and scientific interest in understanding the potential role of environmental factors in elevating BC risk. The question we raise in this review regards the role of environmental factors, and in particular of pesticides, see Fig. 2.

Fig. 1.

Histopathological and immunophenotypic profile of an invasive breast carcinoma. (A) Hematoxylin–eosin staining shows invasive breast carcinomas NST. (B) Estrogen receptor (ER) immunostaining demonstrates strong and diffuse nuclear positivity in > 90% of tumor cells. (C) Progesterone receptor (PR) is also expressed, with approximately 80% of nuclei showing moderate-intense labeling. (D) Ki-67 reveals a low proliferative index. (E) HER2 immunostaining shows faint, incomplete membranous reactivity corresponding to a score of 1+, consistent with a non-amplified status. (F) The loss of p63 confirms the invasive nature of the lesion. A, B,C, D and F scale bars represent 100 μm. E scale bar represents 50 μm

Fig. 2.

Molecular pathways linking pesticide exposure to breast cancer development. Schematic representation of the main biological processes through which environmental pesticides may contribute to breast carcinogenesis. Endocrine-disrupting compounds activate MAPK/PI3K/AKT signaling, ultimately leading to dysregulation of estrogen signaling. Several pesticides can also trigger oxidative stress, promoting reactive oxygen species (ROS) accumulation, lipid peroxidation, and DNA damage. These alterations converge toward genomic instability and facilitate a pro-tumorigenic microenvironment within breast tissue

Environmental exposures as emerging determinants

Environmental exposures, collectively referred to as the exposome [12], are increasingly recognized as pivotal determinants in BC etiology and progression [13].

Over the last decades, the global dissemination of industrial chemicals, pesticides, plasticizers, and persistent organic pollutants (POPs) has profoundly altered human and ecological health. Many of these compounds act as endocrine-disrupting chemicals (EDCs), interfering with estrogen and androgen signaling, or perturbing transcriptional and epigenetic programs that control cell proliferation and differentiation. Epidemiological and mechanistic evidence now implicates numerous environmental toxicants, including organochlorine pesticides such as, DDT, hexachlorobenzene, and chlordane, and agrochemicals, such as glyphosate and atrazine, in the initiation and progression of breast carcinogenesis [7, 13]. These agents can persist for decades in soil, air, and biota, bioaccumulating in the food chain and in adipose tissue, where they act as reservoirs for chronic low-dose exposure. Even after they have been legally banned, some pollutants continue to be detected in women’s serum and breast tissue, underscoring the long-term persistence of anthropogenic contamination.

The biological plausibility linking environmental contaminants to BC is supported by multiple mechanistic pathways. Many pesticides and POPs display estrogenic or anti-androgenic activity, modulating hormone receptor–dependent transcription and cell-cycle regulators. Others act through non-hormonal routes, inducing oxidative DNA damage, epigenetic reprogramming, mitochondrial stress, and chronic inflammation [13]. Experimental studies have demonstrated that certain compounds, such as bisphenol A [14], phthalates [15], and dioxins [16], promote epithelial-to-mesenchymal transition (EMT) [17, 18], enhance cancer stemness [19], and increase migratory and invasive capacity of BC cells [13]. These mechanisms converge on signaling pathways including ERK, PI3K/Akt, AhR, and TGF-β, which are central to tumor progression, resistance to therapy, and metastatic dissemination.

Population-based studies across the United States, Europe, and Latin America consistently report higher BC risk among women involved in agricultural work, pesticide application, or living near areas of intensive crop spraying [7]. In multiple cohort analyses, direct pesticide exposure has been associated with an approximately twofold increase in breast cancer risk, particularly among women engaged in pesticide application or handling contaminated garments [20, 21]. The feminization of agriculture, a demographic shift that has dramatically increased women’s participation in farming, amplifies this concern, exposing millions of women worldwide to chronic pesticide contact in occupational and domestic contexts [22]. These risks are compounded in regions with limited protective equipment use and insufficient regulation of pesticide residues in food and water.

Beyond chemical toxicants, broader planetary changes are intensifying exposure risks. The 2025 Lancet Countdown on Health and Climate Change highlights how anthropogenic climate disruption, through rising temperatures, droughts, floods, and wildfires, reshapes patterns of chemical use and environmental persistence [23]. Heat extremes and shifting rainfall modify pest dynamics, driving increased pesticide application and volatilization, while droughts and soil degradation enhance the mobilization of persistent compounds into water supplies. Such cascading interactions between climate and pollution magnify the global burden of exposure, particularly in low- and middle-income countries where regulation and surveillance remain weak.

Collectively, these findings indicate that environmental exposures constitute not peripheral but central, modifiable determinants of BC risk. The convergence of chemical pollution, climate change, and social inequities delineates a new frontier in BC prevention. Disentangling the multifactorial effects of the exposome, through integrative molecular epidemiology, multi-omic profiling, and geospatial exposure modelling, will be essential to identify vulnerable populations and develop precision prevention strategies. In this context, acknowledging the environment as a critical determinant of BC is not merely an ecological consideration but an urgent biomedical priority.

Accordingly, this review focuses on elucidating the epidemiological and mechanistic links between pesticide exposure and BC, providing an integrated overview of current evidence and outlining emerging perspectives for risk assessment and preventive action.

Classification of pesticides and human exposure

Major pesticide classes

Pesticides constitute a broad and heterogeneous class of chemical agents formulated to eliminate or control unwanted species, such as weeds, fungi, and insects, that compromise agricultural yield and food storage. Table 1 reports the main pesticide classes according to the international Agency for Research on Cancer (IARC) classification [24]. Based on their chemical structure or intended target, pesticides are typically classified into major groups, including organochlorines, organophosphates, carbamates, triazines, pyrethroids, neonicotinoids, and the non-selective herbicide glyphosate. Each group possesses distinct toxicological profiles, yet many share the capacity to disrupt endocrine homeostasis, generate oxidative stress, and induce genotoxic alterations in human cells [25] (Fig. 2).

Table 1.

Major pesticide classes, IARC classification, associated cancers, and mechanistic evidence

Pesticide class	Representative compounds	IARC classification	Associated cancers	Proposed mechanisms
Organochlorines (OCs)	DDT, DDE, lindane, dieldrin, chlordane	DDT: Group 2 A; Lindane: Group 1	Breast, liver, non-Hodgkin lymphoma	Endocrine disruption, estrogen receptor (ER) activation, oxidative stress, bioaccumulation
Organophosphates (OPs)	Malathion, diazinon, parathion, chlorpyrifos	Malathion & Diazinon: Group 2 A; Parathion: Group 2B	Non-Hodgkin lymphoma, leukemia, possible breast	Acetylcholinesterase inhibition, ER cross-talk, oxidative stress, immune dysregulation
Carbamates	Carbaryl, methomyl, propoxur, aldicarb	Carbaryl: Group 3; others 2B–3	Lung, hematologic, limited breast evidence	Reversible AChE inhibition, endocrine disruption, DNA damage
Triazines	Atrazine, simazine	Atrazine: Group 3	Breast, ovarian (suggestive)	Aromatase induction, ER modulation, epigenetic remodeling
Glyphosate	Glyphosate	Group 2 A	Non-Hodgkin lymphoma; possible breast	Oxidative stress, mitochondrial dysfunction, ER signaling, DNA methylation changes
Dithiocarbamates	Mancozeb, zineb	Group 3	Thyroid tumors, endocrine effects	Metabolite ETU: thyroid toxicity, hormone imbalance
Pyrethroids	Permethrin, cypermethrin, deltamethrin	Group 3	Hematologic, weak breast evidence	Endocrine activity, genotoxicity, oxidative stress
Neonicotinoids	Imidacloprid, clothianidin, thiamethoxam	Group 3	Limited human data; experimental neurotoxicity	Nicotinic receptor interaction, oxidative stress, epigenetic changes
Phenoxy herbicides	2,4-D, MCPA	2,4-D: Group 2B	Non-Hodgkin lymphoma	Oxidative stress, peroxisome proliferation, immune modulation
Urea-derived herbicides	Linuron, diuron	Group 3	Breast, thyroid (experimental)	Endocrine disruption, altered steroidogenesis, hormone metabolism

According to the International Agency for Research on Cancer [24], several widely used organophosphate pesticides and herbicides, malathion, diazinon, and glyphosate, are classified as Group 2 A, probably carcinogenic to humans, whereas tetrachlorvinphos and parathion are classified as Group 2B, possibly carcinogenic to humans. Earlier assessments also identified dichlorodiphenyltrichloroethane (DDT) and related organochlorines as Group 2 A carcinogens, reflecting sufficient evidence of carcinogenicity in experimental animals and limited evidence in humans. These evaluations underscore the biological plausibility that chronic exposure to such compounds, even at low environmental doses, contributes to the initiation or promotion of hormone-dependent cancers such as breast carcinoma [24].

Organochlorines (OCs), including DDT, aldrin, dieldrin, and chlordane, are among the earliest synthetic pesticides. Despite bans in most countries, their high lipophilicity and resistance to degradation render them POPs that bioaccumulate in adipose tissue and human milk. Their ability to bind and activate estrogen receptors, antagonize androgen signaling, and induce oxidative stress implicates them as paradigmatic EDCs contributing to breast tumorigenesis [25].

Organophosphates (OPs), such as chlorpyrifos, diazinon, and malathion, replaced OCs in the 1970s yet introduced novel toxicological challenges. The IARC Working Group concluded that both malathion and diazinon show sufficient evidence of carcinogenicity in experimental animals and limited evidence in humans, with mechanistic data supporting genotoxic and oxidative stress pathways [24]. These agents act by irreversibly inhibiting acetylcholinesterase but also induce estrogenic and mitogenic signaling in mammary cells at sub-toxic doses [26]. Epidemiological studies have demonstrated elevated breast cancer risk among women occupationally exposed to OPs, particularly in agricultural settings.

Carbamates, including carbaryl, methomyl, and propoxur, share mechanistic similarities with OPs but exhibit shorter environmental persistence. Nonetheless, chronic exposure has been linked to neurological and endocrine alterations, and in vitro evidence suggests their capacity to modulate ER transcriptional activity and aromatase expression, thereby enhancing estrogen biosynthesis [26].

Triazines, with atrazine as their archetype, are potent herbicides with widespread agricultural application. Atrazine has been shown to upregulate CYP19A1 (aromatase) and elevate estrogen production in mammary tissue, leading to enhanced ductal proliferation and preneoplastic lesions in animal models [27]. Although the IARC currently classifies atrazine as Group 3 (not classifiable as to its carcinogenicity to humans), accumulating mechanistic evidence supports its role as a potent endocrine disruptor in breast tissue.

Glyphosate, the most extensively applied herbicide globally, was classified by IARC as Group 2 A (probably carcinogenic to humans) based on sufficient evidence of carcinogenicity in experimental animals and strong mechanistic evidence for genotoxicity and oxidative stress [24]. Beyond its redox and mitochondrial effects, glyphosate and its formulations have been shown to activate estrogen receptor–dependent transcription and alter the expression of estrogen-responsive genes, providing a mechanistic link to hormone-sensitive tumorigenesis [28].

Neonicotinoids and pyrethroids, increasingly detected in surface waters and human biological samples, are generally classified as Group 3 (not classifiable as to their carcinogenicity), yet exhibit significant endocrine-modulating potential. Experimental data reveal that these compounds can alter ERα and ERβ signaling, disrupt steroidogenesis, and modulate key proliferative pathways in mammary cells at environmentally relevant concentrations [29].

Overall, the IARC evaluations highlight a concerning pattern: while the chemical evolution of pesticides has reduced persistence and acute toxicity, many modern agents exert subtler molecular effects—endocrine disruption, receptor cross-talk, and epigenetic reprogramming, that may underlie their association with breast cancer. The convergence of epidemiological, toxicological, and mechanistic evidence reinforces the view that pesticides represent not merely environmental contaminants but biologically active determinants capable of shaping hormone-dependent carcinogenesis in exposed populations.

Routes of exposure: dietary, occupational, and environmental

Human exposure to pesticides occurs through multiple, often overlapping, pathways that reflect both occupational proximity and environmental diffusion.

Dietary exposure represents the most widespread route. Pesticide residues persist on fruits, vegetables, and cereals, and bioaccumulate through animal-derived foods. The Environmental Working Group’s analysis of 47 food items identified a dirty dozen list, including apples, grapes, and strawberries, containing the highest concentrations of pesticide residues [29]. Chronic ingestion, even at low doses, contributes cumulatively to the internal body burden, particularly for lipophilic compounds.

Occupational exposure remains predominant in agricultural workers, pesticide applicators, and food industry employees [30, 31]. Farmworkers are exposed through inhalation, dermal absorption, and accidental ingestion, often without adequate protective equipment. A crucial mechanism of domestic contamination is the take-home pathway, whereby residues adhere to skin, hair, and clothing, contaminating homes and increasing exposure among family members, including children [29].

Environmental exposure affects populations far from agricultural zones due to pesticide drift, volatilization, and contamination of soil and groundwater. The long-range transport of persistent compounds explains their detection even in urban and remote regions. In a longitudinal study in Washington State, Bennett et al. [29] detected over 80 distinct pesticides in household dust, including organophosphates and carbamates, both in farmworker and non-farmworker homes, indicating pervasive environmental contamination.

Together, these routes highlight the ubiquity and complexity of human pesticide exposure, blurring the boundary between occupational risk and population-wide environmental vulnerability.

Bioaccumulation and persistence in adipose tissue

A defining feature of many pesticides, especially organochlorines, triazines, and certain fungicides, is their lipophilicity and resistance to metabolic degradation. These properties facilitate bioaccumulation in adipose tissue, which serves as a long-term reservoir, slowly releasing toxicants into circulation over years [32–34].

In women, the breast is both a metabolically active and lipid-rich organ, rendering it particularly susceptible to accumulation of persistent compounds. Several studies have detected measurable levels of DDT, DDE, β-HCH, and heptachlor epoxide in breast adipose tissue and tumor samples [35, 36]. These residues correlate with increased expression of estrogen receptor–regulated genes and oxidative stress markers, suggesting a direct molecular link between stored pesticides and breast tumor biology.

Bioaccumulated pesticides can be mobilized during pregnancy, lactation, and weight loss, periods characterized by enhanced lipolysis and altered hormonal balance. This mobilization increases circulating levels of lipophilic contaminants, exposing the developing fetus or breastfeeding infant during critical windows of susceptibility [37].

The persistence of these chemicals, spanning decades in human tissue, underscores the need to view pesticide exposure as a chronic, lifelong process rather than an isolated event. Within the context of BC, such sustained exposure may amplify hormonal and epigenetic reprogramming, predisposing to neoplastic transformation.

Breast cancer and pesticide

Once accumulated in the fat tissue, pesticides interfere with the cellular homeostatic mechanisms, including redox/hypoxia [38, 39], DNA damage repair and p53 [40, 41] and vascular [42] function, thereby favoring neoplastic transformation and progression (Fig. 2). Long-term exposure to pesticides has been associated with an increased global risk of developing BC [43, 44]. In this context, Huang et al. conducted a case-control study in China analyzing breast adipose tissue from 209 BC patients and 165 controls. Using gas chromatography-mass spectrometry (GC-MS), they quantified DDT metabolites, finding significantly higher levels of p, p′-DDE in cancer patients. These compounds were positively associated with BC risk in a dose-dependent manner, while others like p, p′-DDT showed no significant or inverse associations [45, 46]. These effects may be mediated via nERs, given the estrogenic activity of these lipophilic contaminants. Similar results were obtained using GC with electron capture detection (GC-ECD) to analyze breast adipose tissue from women with malignant and benign conditions [47]. In the study is reported a 50% increase in p, p′-DDE levels in BC patients, reinforcing the hypothesis of a link between chronic exposure to DDT derivatives and breast carcinogenesis [47]. He et al. 2017 also employed GC-ECD to assess six organochlorine compounds, finding elevated levels of p, p′-DDE in cancer patients, although no correlation was observed with tumor biomarkers such as ER, PR, HER2, or Ki-67 [48]. The selective accumulation in tumor tissue was further explored in another study [49] who compared tumor and adjacent non-tumor breast tissues. The analytical technique GC-ECD employed, revealed significantly higher concentrations of α-HCH, γ-HCH, and HE in tumor samples. Moreover, in the same study, correlations between pesticide levels and antioxidant enzyme activity were found, suggesting that oxidative stress may be a contributing factor in tumor development [49]. A cross-sectional recent study conducted in North India confirmed these findings [50], showing elevated levels of β-HCH, heptachlor, dieldrin, and p, p′-DDE in tumor-associated adipose tissue. Notably, p,p′-DDE was detected in all tumor samples, often exceeding 2600 ppb. While no significant correlations were found across the entire cohort, a positive association between OCP concentrations and PR expression was observed in ERα-positive tumors. In post-menopausal women, higher pesticide levels were linked to increased Ki-67 expression, indicating enhanced proliferative activity [50]. Medina et al. developed a highly sensitive GC-MS/MS method combining EI and Negative Chemical Ionization (NCI) modes to detect multiple halogenated pollutants in breast tissue. Their results confirmed substantial bioaccumulation of p, p′-DDE, β-HCH, and PBDE-47 in BC samples, with concentrations reaching up to 1200 ng/g for p, p′-DDE [51]. These findings align with those reported by Güttes et al., that compare malignant and benign breast tissues, reporting significantly higher levels of p, p′-DDE in cancerous samples [52]. Further supporting the lipid affinity of these compounds, another study [53] showed that pollutant concentrations were consistently higher in breast adipose tissue than in serum, emphasizing their tendency to accumulate in lipid-rich environments. Ociepa-Zawal et al. 2010 confirmed this pattern, detecting OCPs in all samples from women with invasive BC, with p, p′-DDE, β-HCH, and HCB frequently exceeding 2600 ppb [54]. Interestingly, it has been demonstrated that some compounds such as γ-HCH and p, p′-DDD were more abundant in benign tumors, suggesting a complex and context-dependent relationship between pollutant accumulation and tumor biology [55]. Table 2 reported the main studies concerning the accumulation of pesticides in breast tissues.

Table 2.

Studies reporting persistent organic pollutants in breast tissue

Analyzed Compounds	Detected Concentrations	Analytical Techniques	Reference
p, p′-DDE	Elevated in BC patients	GC-MS	[45]
p, p′-DDT	No significant or inverse associations	GC-MS	[46]
p, p′-DDE	+ 50% in BC patients	GC-ECD	[47]
p, p′-DDE	Elevated in BC patients	GC-ECD	[48]
α-HCH, γ-HCH, HE	Higher in tumor tissue vs. non-tumor	GC-ECD	[49]
β-HCH, heptachlor, dieldrin, p,p′-DDE	>2600 ppb in all tumor samples	Not specified	[50]
p, p′-DDE, β-HCH, PBDE-47	p, p′-DDE up to 1200 ng/g	GC-MS/MS	[51]
p, p′-DDE	Higher in malignant tissues	Not specified	[52]
Various PoPs	Higher in adipose tissue than serum	Not specified	[53]
p, p′-DDE, β-HCH, HCB	>2600 ppb in all samples	Not specified	[54]
γ-HCH, β-HCH, p,p′-DDD, total DDT	β-HCH predominant in malignant tumors	Not specified	[55]

Due to their ability to disrupt the endocrine system, by interfering with hormonal regulation, promoting oxidative stress, and causing DNA damage that can lead to oncogenic mutations, there is growing international effort to reduce human contact with these substances [56–58]. Compounds such as chlorpyrifos, imazalil, malathion, and thiabendazole have been detected in significant concentrations within breast tumor tissues, suggesting a potential link between environmental exposure and carcinogenesis [59, 60]. These pesticides may contribute to the development of BC through both mutagenic and non-mutagenic pathways, acting either as direct carcinogens or indirectly, by disrupting biochemical processes and hormonal balance. Endocrine disruptor chemicals are of particular concern due to their ability mimic the action of estrogen by binding to nuclear nERs, thereby promoting cellular proliferation and potentially contributing to BC development and progression [61]. These compounds can interact with both ERα and ERβ receptors, activating gene transcription even in the absence of natural estrogen such as 17 β-estradiol (E2) [62]. Typically, ERα is associated with cell proliferation and tumor progression, whereas ERβ is thought to counteract these effects, acting as a tumor suppressor [63]. However, exposure to some EDCs may disrupt this balance, potentially altering ERβ function and converting it into a promoter of tumor growth. Chronic exposure to low doses to these substances, even when levels fall below current regulatory limits, can still exert significant biological effects, particularly during puberty, pregnancy, or menopause [64]. These life stages are characterized by heightened hormonal sensitivity, making the body more susceptible to the disruptive effects of EDC chemicals. More information about estrogen receptor signaling is reported in online supplementary BOX S1.

Pesticides and Estrogen receptor signaling in breast cancer

Chronic exposure to specific pesticides, particularly organochlorines, organophosphates, triazines, and glyphosate-based herbicides, can profoundly affect ER signaling. Molecular data suggest that lindane (γ-HCH), DDT, glyphosate, malathion/diazinon atrazine, carbaryl, and 2,4-D have a strong endocrine-disrupting potential thus suggesting a possible role in breast carcinogenesis. These agents, widely used across agricultural systems, can mimic 17β-estradiol (E2), antagonize its physiological activity, or disturb both genomic and non-genomic estrogen signaling through ERα, ERβ, and G-protein–coupled estrogen receptor (GPER) [24].

Recent in vitro and in vivo findings underscore that estrogenic or antiestrogenic effects arise not only at high occupational doses but also at environmentally relevant concentrations, often within the limits allowed in drinking water. Genome-wide transcriptomic analyses [65] revealed that MCF-7 and MDA-MB-231 cells exposed to glyphosate (50–500 ppb) or atrazine (2–20 ppb) for 72 h exhibited hundreds of differentially expressed genes associated with DNA repair, lipid metabolism, oxidative stress, and ER signaling, despite the absence of overt cytotoxicity. In particular, upregulation of ABCA1, C4B, CP, and OAS2 and downregulation of histone cluster genes (HIST1H4H, HIST1H4E) and UGT2B15 suggest alterations in chromatin remodeling and estrogen metabolism, supporting the concept that chronic micro-exposures can reprogram mammary cells toward proliferative phenotypes.

Epidemiological data corroborate these experimental findings. A cross-sectional Indian study [50] demonstrated significantly higher levels of γ-HCH, endosulfan-II, p,p′-DDT, and p, p′-DDD in breast adipose tissue of cancer patients than in benign controls, with odds ratios of 1.3 and 2.7 for endosulfan-II and p, p′-DDT, respectively. Elevated levels of these OCPs were also associated with lymph node metastasis and advanced tumor stage, implicating these persistent pollutants in both tumor initiation and progression. Consistently, OCPs such as DDT and its metabolite DDE function as weak ERα agonists, activating estrogen-responsive genes including MYC, CCND1, BCL2, and GREB1, thereby enhancing proliferation and survival signaling in hormone-dependent breast cancer cells.

Mechanistically, pesticides interfere with ER pathways at multiple levels [66]. They bind directly to the ligand-binding domain of ERα/β, activate ERK/MAPK and PI3K/AKT cascades through membrane-associated ERα36 or GPER, and alter aromatase expression in stromal cells, increasing local estrogen synthesis (e.g. atrazine-mediated CYP19A1 upregulation). Glyphosate and triazines further perturb epigenetic regulation by promoting histone modification and DNA methylation of ER-related genes [67–69]. Toxico-proteomic profiling in chronically exposed women revealed downregulation of ER-mediated signaling together with inflammatory and metabolic reprogramming, correlating with poor prognosis and endocrine therapy resistance [70].

Taken together, these findings outline a coherent pathogenic model in which persistent and emerging pesticides act as multi-modal endocrine disruptors, capable of mimicking estradiol at nanomolar doses, amplifying both genomic and extranuclear ER signaling, inducing oxidative and epigenetic stress, and progressively leading to receptor desensitization and loss of hormonal control. The result is a sustained proliferative stimulus that promotes luminal-to-basal plasticity, metastatic potential, and endocrine resistance. Integrating this mechanistic insight with IARC carcinogenic classifications and molecular epidemiological evidence highlights the urgent need to reassess chronic pesticide exposure as a determinant of hormone-dependent breast cancer risk.

Pesticides and oxidative stress in breast cancer

Reactive oxygen species (ROS) generated during the biotransformation of organophosphates, organochlorines, and triazine herbicides act as molecular triggers of lipid peroxidation, DNA oxidation, and redox imbalance, processes that promote genomic instability and malignant transformation, see Fig. 2 [71]. Oxidative stress has emerged as a key intermediary between environmental pesticide exposure and the dysregulation of hormonal and proliferative signaling pathways that drive breast cancer. In this context, xenobiotic-metabolizing enzymes (XMEs), including the cytochrome P450s (CYP2E1) and phase II detoxification enzymes such as glutathione S-transferases (GSTM1, GSTT1) and UDP-glucuronosyltransferases (UGT2B7), play a pivotal role in modulating pesticide-induced oxidative burden. Polymorphisms or deletions within these genes have been associated with an impaired capacity to neutralize electrophilic metabolites, enhancing oxidative damage and cancer susceptibility among exposed individuals [72].

Recent clinical and molecular studies have provided direct evidence of these associations. In a large cohort of Indian agricultural workers occupationally exposed to pesticides, Pandiyan and colleagues [73] demonstrated that individuals carrying null alleles for GSTM1 or GSTT1 exhibited markedly elevated serum 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, and an increased risk of BC (OR = 6.88, 95% CI: 1.88–25.99). Similarly, polymorphisms in CYP2E1, involved in the oxidative metabolism of organophosphates, were correlated with enhanced oxidative stress and higher cancer prevalence, underscoring the synergistic effect of genetic susceptibility and pesticide exposure on redox homeostasis. Complementing these findings, Vacario et al. [72] reported that occupational pesticide exposure potentiates lipid peroxidation and nitric oxide (NOx) production in plasma of breast cancer patients, particularly in carriers of the UGT2B7 rs7438135 (G >A) variant, while concomitantly depleting the total antioxidant capacity (TRAP). The inability of this polymorphism to confer protection against oxidative damage suggests that genetic variation may influence not only detoxification efficiency but also systemic responses to oxidative stress.

At the tissue level, it has been demonstrated that women chronically exposed to agricultural pesticides, predominantly glyphosate, atrazine, and 2,4-D, exhibit a distinct inflammatory and oxidative stress signature even in histologically normal breast tissue [74, 75]. The exposed group showed reduced TRAP levels, increased lipid peroxidation, and elevated TNF-α, suggesting that oxidative imbalance precedes tumor development and may prime mammary epithelial cells toward pro-tumorigenic pathways. This pre-neoplastic redox dysregulation parallels findings in experimental models, where oxidative stress mediates pesticide-induced activation of NF-κB and peroxisome proliferator-activated receptor-γ (PPARγ), both of which regulate cytokine release, proliferation, and apoptosis resistance. Notably, fungicides such as fenhexamid have been shown to activate ERα and upregulate lipogenic and antioxidant-response genes, including PPARγ, SREBP1, and FABP4, further linking endocrine disruption to metabolic reprogramming and redox imbalance [76].

From molecular point of view, pesticide-induced oxidative stress interacts with hormonal signaling to amplify breast cancer risk [77–80]. ROS can activate mitogen-activated protein kinases (MAPKs) and PI3K/AKT cascades, which, in turn, phosphorylate and stabilize ERα, promoting ligand-independent activation. This crosstalk enhances transcription of pro-proliferative genes (CCND1, BCL2) and suppresses apoptotic checkpoints, while chronic oxidative conditions foster mutations in tumor suppressor genes and methylation of detoxifying enzyme promoters, further exacerbating oxidative susceptibility. The accumulation of lipid peroxides and NOx not only damages membranes and DNA but also acts as a persistent inflammatory stimulus, supporting angiogenesis and tumor progression.

Conclusive remarks

The evidence reviewed in this manuscript highlights the potential role of pesticides, particularly those classified as EDCs, in the pathogenesis of BC. Numerous studies have demonstrated that these compounds, due to their lipophilic nature and environmental persistence, tend to bio-accumulate in adipose-rich breast tissue, including areas adjacent to tumors. Their frequent detection at elevated concentrations in malignant tissues, compared to benign counterparts, suggests a possible involvement in tumor initiation or progression. Mechanistically, EDCs such as OCPs are known to interact with estrogen receptors (ERα, ERβ, and GPER1), potentially disrupting hormonal homeostasis and activating both genomic and non-genomic signaling pathways. Even at low doses, these compounds may promote cellular proliferation, inhibit apoptosis, and contribute to a pro-tumorigenic microenvironment. This is particularly concerning during puberty, pregnancy, or menopause, when hormonal regulation is especially sensitive. Given the consistent detection of these pollutants in breast tissue and their potential to interfere with endocrine function, the identification and quantification of pesticide residues in biological samples represent a crucial step toward understanding environmental contributions to BC. These findings highlight the urgent need to improve biomonitoring strategies and consider environmental factors more explicitly in cancer prevention and public health policies. Lastly, integrating environmental toxicology with cancer research [81–84] may open new avenues for risk reduction, early detection, and targeted therapeutic intervention.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

DM, AM, GM and MS conceived the project; DM wrote the first draft; all authors wrote the final manuscript; MS prepared figures and tables. All of the Authors have approved this submitted version.

Funding

This work has been supported by the European Union NextGenerationEU via MUR-PNRR M4C2-II.3 PE6 project PE00000019 Heal Italia (CUP: E83C22004670001) to G.M., Associazione Italiana per la Ricerca contro il Cancro (AIRC) to GM (IG 2022 ID 27366; 2023–2027), to EC (IG#31044; 2024–2029); Ministry of Health - HUB LIFE SCIENCE – Advanced Diagnostic- Italian network of excellence for advanced diagnosis (INNOVA) (PNC-E3-2022-23683266) to GM, AM, MS; Fondazione Luigi Maria Monti IDI-IRCCS (R.C. to E.C.).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Competing interests

GM and YS are members of the Editorial Board of Biology Direct.