Breast cancer remains the most commonly diagnosed malignancy among women worldwide and exhibits pronounced heterogeneity and metastatic potential, contributing to substantial variation in clinical outcomes [1]. While established risk factors include ionizing radiation exposure, hormone replacement therapy, and germline mutations in BRCA1/2 [2], a growing body of evidence suggests that environmental exposures may also play a critical—yet underexplored—role in breast cancer etiology.

Epidemiological studies have linked these chemicals to breast carcinogenesis, primarily via estrogen receptor (ER) signaling interference [3]. However, many of these compounds exert their oncogenic effects only after prolonged, low-dose exposure, posing a challenge for traditional in vitro models, which often fail to replicate the biological consequences of chronic exposure within realistic timeframes [4].

To address these challenges, several innovative approaches have been developed to explore the potential causal relationships and mechanisms underlying environmental exposures and disease. Among these, Mendelian randomization (MR) is a powerful analytical tool that utilizes genetic variants as instrumental variables to infer causality between exposure and disease outcomes. In parallel, network toxicology—rooted in systems biology—integrates multidimensional data on toxicants, protein targets, and biological pathways to systematically unveil molecular mechanisms underlying toxic effects.

Of particular interest is the ubiquitous use of preservatives in consumer products and their emerging health risks. Methylparaben (MEP), commonly used in food processing and cosmetics, has long been considered safe. However, growing evidence suggests that MEP may act as an environmental pollutant with underexplored toxicological properties. Retrospective studies have shown that parabens—used as preservatives in thousands of consumer products [5], [6]—can be readily absorbed through the skin and detected in human plasma shortly after use. The number of personal care products used has been positively correlated with paraben concentrations in blood and urine [7], [8], [9], [10]. In 2004, parabens were first detected in human breast tumor tissue [11], raising questions about their role in breast cancer pathogenesis.

Subsequent studies revealed that parabens exhibit estrogenic activity and can stimulate the proliferation of estrogen receptor-positive (ER+) breast cancer cells [12]. Moreover, their interaction with members of the human epidermal growth factor receptor (HER) family has been shown to amplify their oncogenic effects in breast cancer cells [13]. Beyond proliferation, parabens have been implicated in enhancing the migratory and invasive properties of breast cancer cells, processes that are central to metastasis [14]. These tumor-promoting effects have been validated across various breast cancer cell lines, with particularly pronounced effects observed in cell lines derived from individuals of West African ancestry [15].

While prior studies have predominantly focused on the estrogenic activity of parabens, accumulating evidence suggests that MEP may exert additional oncogenic effects through non-classical pathways. These include interactions with growth factor receptors, intracellular kinases, and transcription factors unrelated to estrogen signaling [12], [13]. Therefore, this study also sought to investigate the potential for MEP to promote breast cancer progression via non-estrogenic molecular mechanisms.

However, the concentrations required to induce proliferation in vitro often exceed physiological levels observed in breast tissue. This discrepancy suggests that MEP may pose a latent risk for breast cancer development. Nevertheless, the precise mechanisms by which MEP might initiate or promote breast cancer remain largely unknown. This study aims to elucidate the association between MEP exposure and breast cancer progression and to dissect the underlying molecular mechanisms.