Breast cancer remains one of the most prevalent malignancies affecting women worldwide, with growing evidence linking its incidence to dietary factors. Several epidemiological studies and meta-analyses have examined associations between soy isoflavone intake and breast cancer outcomes, with some suggesting a modest reduction in overall mortality and recurrence among high consumers of soy isoflavones, particularly in postmenopausal women.1 Current treatment modalities include local interventions (i.e., surgery and radiation therapy) and systemic approaches (i.e., chemotherapy, targeted therapy, hormonal therapy), with therapeutic strategies guided by molecular subtyping.2

Phytochemicals from medicinal plants and herbs exhibit multifaceted cancer-related molecular pathways, including enhancement of detoxification pathways, modulation of hormonal and enzymatic activity, attenuation of treatment-related adverse effects, and immunomodulation through cytokine production (interleukins, interferons, tumor necrosis factor-α, colony-stimulating factors).3

Among natural compounds, soy-derived phytoestrogens have garnered particular interest for their hypothesized cancer risk-modifying potential. The striking geographical disparity in breast cancer incidence—with significantly lower rates in Asian populations (25–50 mg/day isoflavone intake) compared to Western countries (<2 mg/day)—suggests a potential association between soy consumption and breast cancer outcomes.4 Clinical evidence from Shu et al. demonstrated that breast cancer patients consuming soy isoflavones experienced 29% reduction in mortality risk and 32% decrease in recurrence rates. Beyond oncology, soy isoflavones show therapeutic potential for menopausal symptom management, cardiovascular protection, osteoporosis prevention, and urogenital health maintenance.5 Human tumor profiling studies have identified gene expression signatures associated with soy supplementation, including modulation of cell cycle-related transcripts, although such results underscore the context specificity of isoflavone effects and do not establish direct clinical benefit.6

While epidemiological and clinical data support soy’s anticancer effects, the precise molecular mechanisms remain incompletely understood. This study employs integrated bioinformatics approaches to identify differentially expressed genes (DEGs) associated with soy-derived isoflavone exposure in experimental breast cancer, characterize affected signalling pathways, and elucidate potential therapeutic targets.

Breast tissue homeostasis relies on a precise balance between cell proliferation and apoptosis. Tumorigenesis arises not only from uncontrolled proliferation but also from impaired apoptosis, a process targeted by conventional therapies (chemotherapy, radiotherapy, and hormonal treatments).7 Soy isoflavones such as genistein and daidzein exhibit complex biological effects, acting through estrogen receptor-dependent and -independent pathways that can influence cell proliferation, apoptosis, and epigenetic regulation in a context-dependent manner.8 Our study elucidates how soy isoflavones modulate key genes and pathways implicated in breast cancer biology under experimental conditions. By integrating data from 4 GEO datasets, we identified DEGs and pathways, revealing transcriptional patterns consistent with modulation of cancer-related pathways under experimental conditions, including enzyme inhibition (5α-reductase, cyclin-dependent kinases), downregulation of oncogenic pathways (NF-κB, Akt, MAPK), and proapoptotic effects (FOXO, JUN, TFPI2, GSN, AKR1C1, WSB1, NEAT1).

Soy isoflavones modulated the expression of genes linked to PI3K/Akt and EMT pathways (upregulation of FOXO, which can oppose Akt signaling in some contexts). However, given the oncogenic roles of these pathways in breast cancer, the net biological implication remains unclear and context-dependent. FOXO, a key regulator of PI3K/Akt, counteracts oncogenic signals driven by PTEN or PIK3CA dysregulation, potentially reducing cell survival and metastasis.9

Similarly, JUN and TFPI2, downregulated in breast cancer but upregulated by soy, modulate EMT, which is critical for invasion and metastasis. JUN is a protein-encoding gene related to breast cancer. Activated C-JUN is often expressed at the invasive front in breast cancer. This gene is related to proliferation and angiogenesis. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition are associated with c-Jun levels.10 Lukey et al.11 argued that JUN’s role in metabolic reprogramming may sensitize cancer cells to targeted therapies, suggesting potential biological relevance that warrants further investigation.

GSN, involved in actin cytoskeleton regulation, was also upregulated, potentially limiting cancer cell migration by stabilizing cytoskeletal dynamics. In the research conducted by Biber et al., it was found that perturbations in the regulation of the actin cytoskeleton result in enhanced cancer cell migration, leading to metastatic spread. This paper also explains how the cytoskeleton is a central factor contributing to various hallmarks of cancer. Overall, these findings suggest that GSN may be a promising target for further research into the prevention and treatment of breast cancer.11 Conversely, soy downregulates protumorigenic genes in the cell cycle pathway, including CDC20, CCNB1, CDC6, MAD2L1, CCNA2, TTK, MCM4, CDC25C, MCM2, and ESPL1, shared across 3 studies. These genes, overexpressed in breast cancer, regulate DNA biosynthesis and checkpoints, driving tumor growth.12

Their downregulation by soy suggests transcriptional modulation of cell cycle-related genes under experimental conditions, like healthy tissue expression levels. Additionally, soy-derived isoflavone exposure downregulated protumorigenic genes (NEK2, UBE2C, and TOP2A) linked to the G2/M checkpoint and chromosomal instability, which were suppressed, potentially reducing tumor migration and aneuploidy. In various human breast cancer cell lines, NEK2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. This gene plays a pivotal role in breast cancer growth at primary and secondary sites and may thus be an attractive and novel therapeutic target for this disease.13 UBE2C is an important part of the ubiquitin-conjugating enzyme complex. In cancers with a high degree of malignancy and tendency to metastasize and poor differentiation, UBE2C expression is usually higher, and patient survival is poor. It has been shown that UBE2C is highly expressed in BRCA, which confirms the prognostic significance of UBE2C in BRCA.14,15

GTSE-1 is another gene which is upregulated in breast cancer patients, but is downregulated by soy-derived isoflavones, and is also present in the P53 pathway. GTSE-1 is specifically expressed during the S and G2 phases of the cell cycle. Studies have proven that GTSE1 can affect the AKT pathway to facilitate the growth of breast cancer cells and can increase the metastasis of breast cancer cells by regulating the EMT pathway.12 GTSE1 is associated with increased tumor proliferation and metastasis in breast cancer and contributes to multidrug resistance in breast cancer cells. Considering the function of GTSE1, its potential as a new biomarker for assessing breast cancer progression is important.16

Soy’s impact extends to the immune microenvironment and angiogenesis. The expression of the AKR1C1 gene increased in experimental breast cancer datasets. Upregulation of AKR1C1 and TFPI2 suggests enhanced immune responses and reduced angiogenesis, respectively, consistent with transcriptional changes associated with growth-regulatory processes.17 NEAT1 is another gene overexpressed in patients who consume soy. This gene is involved in rhythmic biological processes and immunity, innate immunity, transcription, and regulation of transcription. It has been shown that its regulation is disturbed in various solid cancers. NEAT1 overexpressed in triple-negative breast cancer, was normalized by soy, potentially improving chemosensitivity.18 These findings highlight soy isoflavones as a potential molecular target requiring validation in controlled experimental and clinical studies. Soy-induced normalization of NEAT1 levels could improve therapeutic responses.

Importantly, the present study does not establish causality between dietary soy intake and breast cancer outcomes, but rather highlights transcriptional signatures observed following isoflavone exposure under experimental conditions.

This integrative bioinformatics analysis identifies transcriptional signatures associated with soy-derived isoflavone exposure in breast cancer models. The observed gene expression patterns suggest modulation of pathways related to cell cycle regulation and apoptosis; however, these findings are exploratory and do not establish therapeutic efficacy. Experimental validation is required to determine the biological and clinical relevance of these observations.