The PI3K/AKT signaling pathway is the hub of cell survival circuitry, proliferative output and cell-cycle regulation. Repression of this axis is a promising strategy for blunting BC progression. Substantial evidence has demonstrated that the PI3K/AKT signaling pathway plays a crucial role in the progression of BC, contributing to numerous cellular processes, including cell growth, angiogenesis, proliferation and metastasis. Components of this pathway are often dysregulated during the progression of BC. Loss of phosphatase and tensin homolog (PTEN), activating mutations in PIK3CA and alterations in AKT can lead to persistent activation of the PI3K/AKT signaling pathway. These changes appear in many subtypes, including HR-positive/HER2-negative, HER2-positive and triple-negative breast cancer, making PI3K/AKT a promising target for a new therapeutic opportunity. Numerous studies have documented the potency of polyphenols. They act as crucial modulators in the PI3K/AKT axis.

Metformin synergizes with dendrosomal nano-curcumin to inhibit mTOR complex 1 signaling, induce S-phase arrest and activate Bax/Bcl-2-mediated apoptosis in BC cells (14). Polydatin (PD) is the glucoside form of resveratrol. PD is being investigated as a strategy to mitigate the side effects induced by sorafenib and to cope with multidrug resistance in cancer. A study revealed that combining the two agents exerted enhanced anticancer effects in BC cells by repressing the PI3K/AKT/mTOR pathway and reducing therapeutic resistance (15). Further work has shown that biochanin A inhibited BC cell survival and induced apoptosis through the mitochondrial route, while simultaneously attenuating PI3K/AKT signaling and regulating cell cycle markers (16). Li et al (17) showed that sinigrin impeded BC cell proliferation by inhibiting PI3K/AKT/mTOR phosphorylation, thus inducing cell cycle arrest. Another study suggested that capsaicin reduced BC cell viability, induced G2/M cell cycle arrest, decreased cyclin-dependent kinase (CDK)8 levels, inhibited PI3K/AKT phosphorylation, and reduced Wnt and β-catenin levels (18).

Taken together, these studies suggest that PI3K/AKT/mTOR inhibition is a recurrent mechanism of several polyphenols in BC models. However, most evidence is based on selected cell lines or xenograft models and the relative contribution of PI3K/AKT suppression to the overall antitumor effect often remains difficult to separate from parallel effects on apoptosis, oxidative stress, cell-cycle arrest and therapeutic resistance pathways.

The molecular basis of cancer pathophysiology remains incompletely understood, yet an important focus of oncology research is tumor-suppressor proteins, particularly the p53 family. p53 is involved in a range of antitumor mechanisms, including the induction of cell-cycle arrest, apoptosis and senescence, as well as the suppression of proliferative signaling. Polyphenols, especially the catechins in green tea, have attracted increasing attention for their ability to modulate p53-related signaling.

Santos et al (19) reported that green tea extract (GTE) suppressed BC cell growth by inducing p53 signaling and inhibiting BC cell migration. Notably, GTE was effective in reducing MDA-MB-231 and MCF-7 cell migration. GTE was associated with decreased p21 and p53 expression in MDA-MB-231 cells, whereas the opposite pattern was observed in MCF-7 cells, along with an altered subcellular distribution of mutant p53. These findings support the potential anticancer activity of GTE on BC cells. Metastatic BC remains a major cause of cancer-related mortality despite advances in systemic therapy. In BALB/c mice bearing aggressive 4T1 BC tumors, chlorogenic acid (CGA) induced apoptosis through p53-mediated signaling (20). Abdel-Latif et al (21) revealed that methoxylated quercetin glycoside (MQG) showed potential anticancer activity, enhancing immune recognition of tumor cells and reducing TNBC-associated markers. MQG-mediated modulation of the p53 pathway altered the oncogenic and immunogenic profiles of BC. However, further clinical studies are needed to fully assess its therapeutic potential. Elsayed et al (22) developed a novel encapsulated chitosan-quercetin-functionalized copper oxide nanoparticle and showed its potential in rat models of BC by modulating p53.

Overall, these findings indicate that p53-related regulation may represent an important mechanism by which polyphenols induce apoptosis, senescence, cell-cycle arrest and tumor-suppressive responses in BC. Nevertheless, the effects of polyphenols on p53 signaling may be influenced by the p53 status of the experimental model, as wild-type and mutant p53 can produce different biological outcomes. Therefore, future studies should distinguish whether polyphenols restore wild-type p53 function, modulate mutant p53 behavior or activate p53-independent mechanisms.

BC progression and metastasis are regulated by multiple signaling axes. Of note, the NF-κB signaling pathway is important. This pathway comprises a family of sequence-specific DNA-binding factors. It regulates various biological processes, including viral infection, inflammatory diseases and oxidative stress, as well as metabolic disorders and cell proliferation. In BC, dysregulated NF-κB signaling modulates cell proliferation, differentiation, angiogenesis, metastasis and apoptosis. Furthermore, previous research has revealed that pharmacological inhibition of aberrantly activated NF-κB can induce apoptosis and suppress metastasis in BC cells. Thus, developing effective inhibitors of NF-κB offers a potential strategy for BC treatment.

CGA has been reported to inhibit BC growth through suppression of NF-κB signaling. CGA markedly blunted the NF-κB and EMT signaling axis. Its antitumor efficacy was assessed in a subcutaneous mouse tumor model. CGA significantly retarded BC growth and improved survival in tumor-bearing mice (23). CGA enhanced antitumor immunity, exerting its antitumor effects by inhibiting NF-κB/EMT signaling. This research demonstrated that CGA is a promising candidate for BC treatment. Capsaicin is a natural product derived from chili peppers. It has attracted increased interest for its anticancer effects, particularly in BC. The proto-oncogene factor that binds to inducer of short transcripts 1 (FBI-1), also known as zinc finger and BTB domain-containing protein 7A, can repress multiple tumor-suppressor genes and promote BC progression. Capsaicin markedly repressed proliferation and triggered apoptosis in BC, as evidenced by caspase 3 activation, increased Bax protein expression and reduced FBI-1 protein expression. Furthermore, FBI-1 overexpression significantly alleviated the pro-apoptotic effect. In addition, as a target gene of FBI-1, NF-κB signaling was also suppressed, with capsaicin reducing p65 nuclear translocation, which was perceptibly increased with FBI-1 silencing or decreased with FBI-1 overexpression (24). Therefore, targeting the FBI-1/NF-κB axis may contribute to the anticancer activity of capsaicin in BC. Zhang et al (25) revealed that curcumin, by acting on the NF-κB/ubiquitin-proteasome system axis, improved muscle atrophy in TNBC cachexia mice. Dietary genistein markedly ameliorated systemic inflammation, obesity and metabolic disorders in ovariectomized mice (26). Of note, it also repressed tumor growth. Within the tumor microenvironment, genistein curbed the recruitment of M2d macrophages and the generation of cancer-associated adipocytes. In vitro, genistein blocked the transition of adipocytes and reduced inflammatory factor production by activating the peroxisome proliferator activated receptor (PPAR)-γ pathway and reducing NF-κB. Furthermore, it impaired the acquisition of invasive properties and EMT in BC cells by interrupting the Wnt3a/β-catenin pathway. Dietary genistein also exerted potent therapeutic activity against TNBC by reshaping epigenetic mechanisms. These findings suggest that this soybean-derived bioactive compound may have potential as a supportive strategy for BC management (27). Notably, the PPAR-γ inhibitor T0070907 reversed the influence of genistein in the coculture system, supporting the involvement of PPAR-γ-dependent mechanisms. This research suggested that genistein could mitigate the side effects of obesity on BC by regulating the microenvironment of the tumor (26). Collectively, these data provided new evidence on how a soy-based diet and genistein intake can reduce BC risk. The inhibitor of NF-κB (IKK) complex is a critical regulator of NF-κB signaling. Pterostilbene-isothiocyanate (PTER-ITC) selectively impaired NF-κB activation in malignant cells (28). It hindered NF-κB/p65 activation and its subsequent nuclear translocation, contributing to the transcriptional repression of NF-κB target genes. PTER-ITC disrupted IKK complex formation and inhibited the interaction between the IKK complex and IKK kinase regulatory subunit gamma, which is central to NF-κB activation.

Overall, these findings support the role of NF-κB as an important inflammatory and survival-related target of polyphenols in BC. Nevertheless, because NF-κB signaling is closely connected with EMT, immune regulation, oxidative stress and the tumor microenvironment, future studies should distinguish direct inhibition of NF-κB signaling from secondary changes caused by broader anti-inflammatory or cytotoxic effects.

The STAT family consists of 7 transcription factors, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These proteins are among the key transcriptional regulators involved in BC biology. These proteins share a highly similar architecture and share a conserved domain structure comprising six functional regions. STAT3 is particularly important because it promotes tumor metastasis, multidrug resistance and sustained proliferation (29). A growing body of preclinical data demonstrates that increased expression and persistent activation of STAT3 fuel BC progression, cell proliferation, metastasis and chemoresistance.

Previous research showed that epigallocatechin-3-gallate (EGCG) repressed adipose-derived mesenchymal stem cell differentiation into adipocytes and disrupted paracrine oncogenic regulation of the invasive phenotype of TNBC cells via STAT3 suppression (30). Quercetin suppressed high-glucose-induced BC progression by targeting the IL6/JAK1/STAT3/MMP9 pathway (31). It reduced proliferation, resistance to apoptosis, EMT and metastatic potential in vitro and in diabetic tumor models. These findings support quercetin as a potential STAT3-targeting polyphenol for BC associated with diabetic comorbidity. Several epimedium-derived flavonoids, including icariin and icariside I, have been reported to regulate JAK/STAT3-related signaling in BC models. Icariin inhibited TNBC proliferation, invasion and pulmonary metastasis (32). Mechanistically, icariin downregulated spindle apparatus coiled-coil protein 1 and suppressed JAK2/STAT3 phosphorylation. Icariside I inhibited BC cell growth, migration, invasion and lung metastasis (33). It suppressed IL-6/STAT3 activation, reduced Cyclin D1, CDK4, Bcl-2, MMP9 and vimentin, and increased Bax and cleaved caspase-3, supporting its STAT3-targeting anticancer potential in BC. 5-Desmethylsinensetin inhibited BC stem cell proliferation and mammosphere formation (34). It reduced CD44/CD24, aldehyde dehydrogenase 1, Oct4, c-Myc, Nanog homeobox and CD44 by suppressing STAT3/IL-6 and STAT3/Yes-associated protein (YAP)1 signaling.

These studies indicate that STAT3 may represent a central convergence point linking cytokine signaling, tumor-cell survival, invasion, immune regulation and therapeutic resistance in BC. However, compared with PI3K/AKT or NF-κB, the current evidence regarding polyphenol-mediated STAT3 regulation remains relatively limited. Further studies are needed to clarify whether polyphenols directly inhibit STAT3 phosphorylation and dimerization, or indirectly modulate STAT3 activity through upstream regulators.

Mammary gland development is normally regulated by several pathways, including Wnt, estrogen, Hedgehog and Notch signaling. However, dysregulation of these signaling pathways can contribute to cancer development, and increased Wnt activity, along with elevated β-catenin abundance, is associated with BC development and progression. In addition, β-catenin-dependent Wnt signaling is frequently activated in TNBC and is associated with poorer overall survival in patients with BC. Numerous studies have focused on the effect of polyphenols to suppress BC development and progression by modulating crucial cell survival pathways (35).

Xue et al (36) showed that CGA binds to low density lipoprotein receptor related protein 6 (LRP6), a coreceptor in the Wnt/β-catenin pathway, and decreases total LRP6, phosphorylated LRP6 (p-LRP6) and β-catenin levels in MCF-7 BC cells. One study showed that targeting CD73 with flavonoids could suppress cancer stem cells (CSCs) and boost lymphocyte influx in TNBC mice through Wnt signaling (37). They identified that luteolin and quercetin showed high binding affinity for CD73. The combination of luteolin and quercetin with paclitaxel (PTX) effectively reduced CSC-promoting pathways, including YAP, PTX-increased CD73 expression and Wnt signaling. CD73 is essential for maintaining the CD44high/CD24low CSC population, and co-targeting YAP, CD73 and Wnt signaling effectively suppressed TNBC progression. Furthermore, this combined treatment repressed PTX-enriched CSCs while promoting lymphocyte infiltration in syngeneic TNBC. A stilbenoid-flavanone hybrid with a polyphenol-like structural scaffold inhibited Wnt/β-catenin signaling and induced G2/M cell-cycle arrest and apoptosis (38). Although mechanistic validation was conducted in colon cancer cells, its activity against breast tumor cells suggests potential relevance for BC-related Wnt/β-catenin targeting. Curcumin nano-chitosan reduced microRNA (miR-221), miR-222 and β-catenin expression in MCF-7 and MDA-MB-231 cells. It also increased Wnt inhibitory factor 1 expression (39). These findings suggest that curcumin nanoparticles may inhibit BC progression partly through miRNA-mediated Wnt/β-catenin pathway regulation.

Taken together, the available evidence suggests that Wnt/β-catenin signaling is an important pathway through which polyphenols may suppress BC cell stemness, proliferation, EMT and metastasis. However, Wnt/β-catenin signaling often interacts with other oncogenic pathways, including PI3K/AKT, NF-κB and estrogen-related signaling. Therefore, the antitumor effects observed after polyphenol treatment may reflect broader network regulation rather than isolated Wnt/β-catenin inhibition. Further studies using pathway-specific rescue experiments and genetic validation are needed to confirm the causal role of Wnt/β-catenin modulation.

The MAPK signaling pathway serves as a crucial mediator linking extracellular stimuli to intracellular responses, thereby influencing gene expression and epigenetic regulation. MAPKs govern fundamental cellular processes. MAPKs mainly include JNK, ERK1/2 and p38. Additionally, the MAPK signaling pathway plays a critical role in BC chemoresistance. Therefore, targeting the MAPK pathway represents a potential strategy for overcoming drug resistance and enhancing the efficacy of anticancer agents in BC.

Wei et al (40) reported that combining quercetin with sulforaphane could inhibit BC cell growth by activating the ERK/MAPK signaling pathway. Ziziphus spina-christi (ZSC) is a kind of medicinal plant rich in polyphenolic bioactive compounds. It contains multiple bioactive constituents and it exerts substantial biological effects, including cytotoxicity. A study reported that ZSC extract repressed cell migration and proliferation in HER2-positive BC through the p38 MAPK signaling axis (41). Inhibition of p38 and JNK was associated with reduced tumor progression and enhanced therapeutic efficacy. Anhydroicaritin showed selective cytotoxicity against ER-positive BC cells (42). It may act through estrogen receptor 1 regulation. It reduced ERα phosphorylation, inhibited MAPK signaling and induced apoptosis. These findings suggest its potential as a subtype-specific lead compound for ER-positive BC. Khongsti et al (43) reported that genistein reduced secreted osteopontin expression and suppressed colony formation, migration and invasion in metastatic breast cancer cells, including MDA-MB-231 cells. Mechanistically, MAPK signaling and SIRT1 activation contributed to these effects. Another study demonstrated quercetin exerted its anticancer efficacy by promoting apoptosis and regulating the MAPK/ERK signaling in the MDA-MB-231 BC cell line (44). Polyphenol-rich Crataegus oxyacantha berry extract inhibited proliferation in MCF-7 and MDA-MB-231 BC cells. It induced G1/S cell-cycle arrest. It downregulated Wnt pathway agonists and upregulated Wnt antagonists (45). These findings suggest potential anti-BC effects through regulation of the canonical Wnt/β-catenin pathway.

Although the above pathways are discussed separately for clarity, they should not be interpreted as independent, linear cascades in BC. PI3K/AKT/mTOR, Wnt/β-catenin, MAPK, IL-6/JAK/STAT3, TNF-α/NF-κB and p53-related signaling form an interconnected regulatory network that jointly controls proliferation, apoptosis, inflammation, EMT, invasion, metastasis and therapeutic resistance (46). For example, PI3K/AKT/mTOR and Wnt/β-catenin signaling both converge on proliferative regulators such as Cyclin D1 and c-Myc, whereas STAT3, NF-κB and MAPK signaling jointly contribute to inflammatory signaling, survival, invasion and metastatic progression (29). The p53-related pathway further intersects with these oncogenic cascades by regulating p21-mediated cell-cycle arrest, apoptosis-related molecules and genomic stability. Therefore, the antitumor effects of polyphenols should be understood as network-level regulation rather than modulation of any single isolated pathway.

Across available studies, several polyphenols, including curcumin, resveratrol, EGCG, quercetin, genistein, apigenin and luteolin, appear to regulate multiple pathways simultaneously. This multi-target property may partly explain their broad effects on BC cell proliferation, apoptosis, inflammation, EMT, metastasis and drug resistance. However, this property also complicates mechanistic interpretation. A reduction in cell viability or tumor volume cannot always be attributed to one specific pathway unless supported by pathway-specific inhibition, rescue experiments, genetic validation or pharmacological controls. Therefore, pathway-level conclusions should be interpreted cautiously, particularly when studies rely mainly on changes in protein expression or phosphorylation without functional validation.

Methodological limitations should also be considered when interpreting the current evidence. Most pathway-related findings are derived from in vitro BC cell lines or animal models and the results may be influenced by receptor status, p53 status, metastatic potential, drug sensitivity and the genetic background of the model. Commonly used cell lines, such as MCF-7, MDA-MB-231 and 4T1, represent only selected biological contexts and cannot fully capture the heterogeneity of human BC. In addition, several in vitro studies evaluated polyphenols at relatively high concentrations, including capsaicin, chlorogenic acid and quercetin combined with sulforaphane (18,36,40). The clinical relevance of these findings may be limited by poor solubility, rapid metabolism, low systemic bioavailability and uncertain tissue distribution (6,7). Animal studies provide important in vivo evidence, immune-microenvironment interactions, long-term toxicity or pharmacokinetic behavior.

Overall, the current evidence supports the potential of polyphenols as multi-target modulators of BC-related signaling networks. Nevertheless, most findings remain preclinical and should be interpreted as mechanistic or hypothesis-generating evidence. Future studies should include standardized dosing, pharmacokinetic assessment, subtype-specific models, quantitative pathway validation and clinically relevant endpoints to determine whether the pathway-regulating effects of polyphenols can be translated into meaningful therapeutic benefits for patients with BC.

The therapeutic relevance of polyphenols in BC should be understood within a broader biological context. Although numerous polyphenols have been shown to regulate cancer-related signaling pathways, their biological effects in vivo depend on absorption, metabolism, tissue distribution and interactions with the host microenvironment. Among these factors, the gut microbiota has attracted increasing attention because it can transform dietary polyphenols into bioactive metabolites while being reshaped by polyphenol intake in turn. This bidirectional relationship provides a mechanistic link among diet, microbial metabolism, estrogen homeostasis, inflammation, immune regulation and BC progression (49).

The interaction between polyphenols and gut microbiota may contribute to the efficacy of combination treatment. In a 4T1 TNBC mouse model, dietary quercetin combined with cyclophosphamide showed potential antitumor effects through complementary microbiome- and immune-mediated mechanisms (50). Mechanistically, quercetin reshaped the fecal microbiome and enriched bacteria such as Akkermansia muciniphila, a species previously associated with improved responses to anti-programmed cell death-1 therapy. These findings suggest that quercetin may potentiate chemotherapy partly through microbiome-mediated mechanisms that complement the immunomodulatory effects of cyclophosphamide. Nevertheless, this evidence remains preclinical, and whether such microbiome-centered dietary polyphenol interventions can improve chemotherapy responses in patients with TNBC requires further clinical validation. Natural polyphenols, with their anti-inflammatory and antioxidant properties, may enhance the stability of probiotics in the gut, while probiotics can modulate polyphenol metabolism (51,52). Polyphenols generally exhibit limited absorption in the small intestine, and a substantial proportion reaches the colon, where intestinal microorganisms metabolize them into smaller and often more bioavailable compounds (53). These microbiota-derived metabolites may differ from their parent compounds in membrane permeability, biological stability and ability to regulate cancer-related pathways. For example, ellagic acid can be converted into urolithins, whereas lignans and isoflavones can be transformed into metabolites with estrogen-modulating properties (54). Resveratrol increased the viability of Lactobacilli by 2.1-fold in vitro, and Lactobacillus plantarum converts resveratrol to the glycosylated metabolite piceid (55). This potential synergy warrants further preclinical and clinical investigation, particularly in HR-positive BC and TNBC. Zhu et al (56) demonstrated that quercetin alleviated BC-related depression in a 4T1 tumor-bearing mouse model by reshaping gut microbiota composition, improving abnormal lipid metabolism and targeting the lipid metabolism-related gene prostaglandin-endoperoxide synthase 2. Although this study did not directly evaluate tumor suppression or a combined polyphenol-probiotic intervention, it supports the broader concept that polyphenols can regulate gut microbiota and immune-metabolic pathways in BC-related pathological conditions.

The gut microbiota is also involved in estrogen homeostasis through the estrobolome, a collection of microbial genes capable of metabolizing estrogens (57). Bacterial β-glucuronidase can deconjugate estrogen metabolites, thereby increasing the levels of biologically available estrogens and potentially contributing to estrogen-driven BC progression, especially in postmenopausal women (58). In this context, polyphenols may interact bidirectionally with the gut microbiome. Microbial metabolism can convert dietary polyphenols into bioactive metabolites, such as enterolactone derived from lignans, which may exert estrogen-modulating or anti-estrogenic effects (59). On the other hand, polyphenols may alter the abundance and metabolic activity of bacteria involved in estrogen metabolism, thereby influencing systemic estrogen exposure. This bidirectional interaction may further affect estrogen-driven signaling pathways, including the ERα/PI3K/Akt axis, which plays a crucial role in the progression of HR-positive BC (60).

Polyphenols may also interact with probiotics or microbiota-derived metabolites to enhance anticancer activity. For example, epigallocatechin-3-gallate, a major green tea polyphenol, has been reported to synergize with probiotics partly through inhibition of the EGFR/Src and NF-κB signaling pathways, both of which are closely associated with inflammation and immune dysfunction in BC (50,61). Similarly, microbiota-derived short-chain fatty acids may interact with polyphenols in BC cells. One study showed that quercetin and sodium butyrate each inhibited MCF-7 cell proliferation, while their combination produced a stronger inhibitory effect than either treatment alone (62). These findings suggest that polyphenols and microbiota-derived metabolites may exert antiproliferative effects against hormone-sensitive BC cells. Microbiota-derived metabolites may influence BC progression by regulating oxidative stress, inflammatory signaling, apoptosis, cell-cycle progression and hormone-dependent pathways.

Probiotics and prebiotics may further influence the polyphenol-gut microbiome-BC axis by regulating microbial composition and metabolic activity. Prebiotics are non-digestible substrates that are selectively utilized by host microorganisms and can promote the growth or activity of beneficial intestinal bacteria (63,64). In this context, prebiotics may indirectly affect BC-related biological processes by shaping microbial metabolism, increasing short-chain fatty acid production and enhancing the biotransformation of polyphenols. Multiple experiments have evaluated the synergistic value of combined prebiotic-polyphenol interventions and outlined preliminary translational pathways (65–67). Notably, prebiotics may cooperate with natural polyphenols by improving their microbial metabolism and bioavailability (68). Polyphenols such as quercetin and epigallocatechin-3-gallate have relatively low absorption rates in the small intestine, and a large proportion can reach the colon, where they are metabolized by gut microbiota into bioactive compounds (53). These microbiota-derived metabolites may have improved membrane permeability and biological activity, enabling them to regulate BC-related signaling cascades. In a clinical pilot study, co-administration of inulin and green tea extract increased plasma levels of epigallocatechin-3-gallate metabolites compared with green tea extract alone, accompanied by a reduction in circulating IL-6 levels (69). Although this finding is not BC-specific, it supports the possibility that prebiotics may enhance polyphenol metabolism and systemic anti-inflammatory effects. Of note, polyphenols themselves have also been discussed as prebiotic-like compounds. Plămadă and Vodnar (68) proposed that polyphenols represent an important group of plant-derived secondary metabolites with potential prebiotic effects. As many polyphenols have low bioavailability, they can reach the colon in relatively unaltered forms and interact bidirectionally with intestinal microorganisms. Through this interaction, polyphenols may promote beneficial bacteria and increase the production of beneficial microbial metabolites. However, most supporting evidence remains preclinical, and further human studies are needed to determine whether these prebiotic-like effects can be translated into clinically meaningful benefits.

Overall, the interaction between polyphenols and the gut microbiome provides a biologically plausible link among diet, microbial metabolism, estrogen homeostasis, inflammation, immune regulation and BC progression. However, current evidence should be interpreted cautiously. Most mechanistic findings are derived from cell culture studies, animal models or indirect observational evidence. The composition of the gut microbiota varies considerably among individuals, and the same polyphenol may produce different metabolites depending on microbial background, diet, age, menopausal status, antibiotic exposure and cancer treatment history. Although the polyphenol-gut microbiome-BC axis represents a promising area of research, its clinical relevance requires further validation.

BC remains a major global health challenge despite advances in chemotherapy, endocrine therapy, targeted therapy and radiotherapy. These treatments are frequently constrained by therapeutic resistance, cumulative toxicity and interpatient heterogeneity. In this context, polyphenols have attracted attention as potential adjuvant agents rather than independent substitutes for standard therapies. Among these strategies, the combination of polyphenols with chemotherapy has been most extensively investigated in preclinical BC models. Several polyphenols have been reported to enhance the sensitivity of BC cells to chemotherapeutic agents through regulation of PI3K/AKT, NF-κB, STAT3, MAPK, p53 and apoptosis-related pathways. Radwan et al (70) showed that resveratrol sensitized tamoxifen-resistant BC cells to tamoxifen by downregulating ATP binding cassette transporter-related multidrug resistance genes, modulating miRNAs, increasing reactive oxygen species (ROS) generation and promoting apoptosis. Although resveratrol has been widely proposed as a potential chemosensitizer, recent evidence suggests that its interaction with chemotherapeutic agents is not uniformly synergistic. In MCF-7 BC cells, resveratrol differentially modulated the cytotoxic, antiproliferative, apoptotic and cell-cycle effects of doxorubicin, PTX and cisplatin. The strongest cytotoxic response was observed in the resveratrol-doxorubicin group, whereas the combinations with PTX or cisplatin showed comparatively limited effects under certain experimental conditions (71). This indicates that the therapeutic value of resveratrol may depend on the chemotherapeutic backbone, dose, exposure time and cellular context. Therefore, polyphenol-based combination strategies should be evaluated cautiously, particularly considering their limited bioavailability, uncertain pharmacokinetic behavior and the lack of clinical validation in patients with BC. Liu et al (72) demonstrated that quercetin pretreatment followed by doxorubicin treatment, delivered through reduction-sensitive hyaluronic acid-based mixed micelles, could overcome multidrug resistance in BC by suppressing P-glycoprotein (P-gp) expression, increasing intracellular doxorubicin accumulation and promoting mitochondria-dependent apoptosis. Another study revealed that quercetin enhanced the chemosensitivity of MCF-7 BC cells to 5-fluorouracil by promoting apoptosis, increasing Bax, p53 and caspase-9 activity, decreasing Bcl-2 expression and suppressing colony formation (73).

Beyond chemotherapy, polyphenol-containing natural combinations have also been investigated as adjuvant strategies for endocrine therapy. A study showed that hesperidin, piperine and bee venom enhanced the antitumor effects of tamoxifen in MCF-7 ×enograft-bearing rats by promoting apoptosis, suppressing angiogenesis-related VEGF expression and inducing cell-cycle arrest (74). Polyphenols have also been investigated as radiosensitizers in BC. For example, resveratrol enhanced the response of MCF-7 BC cells to ionizing radiation by reducing antioxidant enzyme activity, promoting ROS accumulation and increasing the expression of apoptosis-related genes such as Bax, p53 and caspase-8 (75). Research using fisetin micelles further supports the potential of polyphenol-based formulations for radiosensitization in BC treatment (76). A recent study showed that resveratrol enhanced the cytotoxic and pro-apoptotic effects of methylene blue-mediated photodynamic therapy in MDA-MB-231 TNBC cells, with stronger effects than either treatment alone (77).

Importantly, not all combinations of chemotherapeutic agents with natural products are synergistic. A previous study showed that dasatinib plus quercetin or piperlongumine failed to prevent chemotherapy-induced trabecular bone loss in mice, suggesting that senolytic strategies may not effectively mitigate this chemotherapy-related adverse effect in BC (78). In a comparative study using MCF-7 and MDA-MB-231 BC cells, doxorubicin-loaded polyquercetin nanoparticles were combined with curcumin, tannic acid or thymoquinone at different ratios. Despite the promising properties of the nanoparticle platform, including high drug loading and sustained release, most combinations were antagonistic according to combination index analysis. Only a few combinations showed synergy and these effects were restricted to MDA-MB-231 cells (79). This study provides an important cautionary perspective: Polyphenol-chemotherapy combinations may produce beneficial, neutral or unfavorable effects depending on the cellular context, compound pairing, formulation and dose ratio. Therefore, claims of synergy should be supported by quantitative combination-index analysis rather than inferred from reduced cell viability alone.

Polyphenols may have potential value as adjuvant agents for conventional BC therapies, particularly in combination with chemotherapy. These findings should be interpreted cautiously, as most evidence is derived from in vitro or animal studies, and clinically relevant issues such as bioavailability, pharmacokinetics, dose optimization, toxicity and potential interactions with anticancer drugs remain insufficiently clarified.

The clinical translation of polyphenols in BC is mainly limited by their intrinsic pharmacological limitations and insufficient clinical evidence. Engineering delivery systems has therefore become an important strategy for improving the therapeutic applicability of polyphenol-based interventions (80). Current delivery platforms are increasingly designed to enhance cellular uptake, improve tissue penetration, enable controlled or stimuli-responsive release, support combination therapy and overcome multidrug resistance (81).

Nanocarrier-based formulations are a major strategy for addressing the poor aqueous solubility and limited cellular uptake of polyphenols. Improving the solubility and intracellular availability of hydrophobic polyphenols represents a fundamental purpose of nanocarrier design. To address the poor aqueous solubility of resveratrol, polymeric micelles based on Pluronic F127 and vitamin E TPGS were developed to enhance its delivery to BC cells. This formulation improved cellular uptake and showed selective cytotoxicity against MCF-7 and MDA-MB-231 cells (82). Natural exosome-like nanovesicles derived from edible tea flowers, which contain abundant polyphenols and flavonoids, have been reported to suppress metastatic BC through ROS-mediated tumor cell damage and gut microbiota modulation (83). These nanovesicles induced intracellular ROS accumulation, mitochondrial dysfunction, cell-cycle arrest and apoptosis, thereby inhibiting BC cell proliferation and lung metastasis while altering the gut microbial profile. This study supports the broader concept that diet-derived polyphenol-containing systems may regulate BC progression through oxidative stress-related and microbiota-associated mechanisms. Targeted nanocarrier systems may enhance the therapeutic relevance of polyphenol-chemotherapy combinations by improving tumor accumulation, controlling the sequence of drug release and reducing drug efflux. Researchers developed hyaluronic acid (HA)-decorated core-shell polydimethylsiloxane (PDMS) nanoparticles for the sequential delivery of doxorubicin and quercetin in BC models. In an MCF-7 ×enograft model, the quercetin-doxorubicin-loaded PDMS-HA nanoparticles achieved stronger tumor inhibition than single-drug-loaded nanoparticles or free drug combinations, with ~65% tumor volume reduction and without obvious systemic toxicity (84). This study supports the potential of nanocarrier-mediated polyphenol-chemotherapy co-delivery for improving tumor targeting, overcoming multidrug resistance and reducing chemotherapy-associated toxicity. In a recent BC study, phenylboronic acid-functionalized resveratrol oligomers were used as active nanocarriers to co-deliver doxorubicin and IR780 for synergistic chemo-photothermal therapy (85). Compared with passive nanocarriers, this design is notable because resveratrol itself contributed intrinsic anticancer activity while also serving as a structural component of the delivery system. The nanoparticles achieved tumor targeting through phenylboronic acid-sialic acid recognition, stimulus-responsive drug release, enhanced cellular uptake and improved in vivo antitumor efficacy. Another study showed that quercetin-loaded solid lipid nanoparticles potentiated the apoptotic effect of etoposide in MDA-MB-231 BC cells by enhancing Bax/Bcl-2 imbalance, increasing p53 and p21 expression, and activating caspase-3 and caspase-9 (86). A nanocochleate gel co-loaded with curcumin and quercetin improved controlled release, ex vivo skin permeation and MCF-7 cell growth inhibition, suggesting a localized delivery strategy for polyphenol-based BC adjuvant therapy (87). Guo et al (88) developed HA-modified, pH/glutathione-responsive polymeric nanoparticles co-delivering PTX and quercetin, which enhanced PTX retention, suppressed P-gp-mediated drug resistance and improved chemotherapy efficacy in drug-resistant BC.

Taken together, these studies indicate that delivery-system engineering is an important strategy for improving the translational potential of polyphenol-based interventions in BC. Compared with free polyphenols, nanocarrier-based systems may enhance solubility, tumor accumulation, cellular uptake, controlled release and combination efficacy in chemo- or photothermal therapy. In particular, co-delivery platforms using quercetin, curcumin or resveratrol may contribute to the reversal of drug resistance and improved antitumor activity. Beyond formulations specifically designed for polyphenols, recent advances in organelle-targeted nanomedicine and intracellular protein degradation technologies may also inspire future translational strategies for polyphenol-based BC therapy. Calcipoptosis-inducing nanoagonists and biomolecular condensate-based protein degradation tools may offer useful conceptual insights for the future development of platforms designed to improve intracellular targeting and modulate cancer-related signaling networks (89,90). However, most current evidence remains preclinical and several challenges still need to be addressed, including carrier safety, long-term biodistribution, batch-to-batch reproducibility, dose standardization and clinical scalability. Future studies should further validate these delivery systems in clinically relevant models and carefully evaluate their pharmacokinetics, toxicity and therapeutic advantages before clinical translation.

Although preclinical studies have extensively demonstrated that polyphenols regulate multiple BC-related signaling pathways, their clinical relevance ultimately depends on evidence from human studies. Therefore, available human evidence should be interpreted cautiously, especially because pharmacokinetic behavior, systemic bioavailability, dose-response relationships, toxicity profiles and interactions with anticancer drugs remain insufficiently defined.

To provide a clearer overview of the available human evidence, Table II summarizes representative clinical studies of polyphenols in BC-related settings. The table summarizes intervention type, study design, population and duration, dose or formulation and major clinical findings. It highlights that current clinical evidence is heterogeneous, with variable compounds, formulations, doses, treatment durations, patient populations and endpoints. Although some clinical studies suggest potential adjuvant or supportive-care value, the therapeutic efficacy, optimal dose, safety profile, bioavailability and clinical applicability of polyphenols in BC require further validation.

A randomized controlled study evaluated the efficacy and safety of curcumin as an adjuvant to standard chemotherapy in women with locally advanced or metastatic BC. Compared with chemotherapy alone, the curcumin-combination group showed a significantly higher objective response rate, both in the intention-to-treat analysis and among patients who completed treatment (91). However, improvements in progression-free survival (PFS) and time to tumor progression (TTP) were modest and the study was limited by its single-center design, relatively small sample size, heterogeneous chemotherapy regimens and lack of detailed pharmacokinetic evaluation. Therefore, although this study supports the potential role of curcumin as a safe adjuvant to chemotherapy, larger multicenter, double-blind, placebo-controlled trials are still required to confirm its clinical benefit. Similarly, Saghatelyan et al (92) evaluated intravenous curcumin combined with paclitaxel in a randomized, double-blind, placebo-controlled clinical trial involving patients with advanced or metastatic BC. The curcumin-paclitaxel group showed a higher objective response rate than the placebo-paclitaxel group. Rajaram et al (93) evaluated soy isoflavone supplements and soy-based dietary intake in Malaysian peri- and postmenopausal women. Overall, neither approach significantly changed mammographic density after 1 year. A larger decline was observed among women closer to menopause. In a randomized, double-blind, placebo-controlled trial, researchers evaluated soy isoflavone supplementation among healthy premenopausal women (94). Soy isoflavones reduced MRI-measured fibroglandular breast tissue in a time- and concentration-dependent manner. This trial suggests that soy-derived polyphenols may have a potential role in BC risk reduction, although further studies are needed to confirm their clinical relevance. Ávila-Gálvez et al (95) found that diet-derived polyphenol metabolites were detectable in breast tumor tissues, with curcuminoids showing p53/p21-mediated antiproliferative, pro-senescent and pro-apoptotic effects in BC cells. Researchers conducted the DIANA-5 randomized trial in 1,542 high-risk BC survivors to test whether a Mediterranean dietary intervention could reduce recurrence (96). The intervention showed that a greater improvement in the Dietary Index was associated with reduced subsequent BC events, suggesting adherence may be critical for dietary benefit. PFS and TTP improvements were modest and non-significant, while safety was acceptable. Passildas Jahanmohan et al (97) conducted a multicenter, randomized, open-label phase II trial in patients with HER2-negative advanced or metastatic BC receiving docetaxel. Oral curcumin at 6 g/day did not improve the objective response rate compared with docetaxel alone, despite good compliance and acceptable safety. Clinical applications of polyphenols require careful evaluation of safety and herb-drug interactions. Braal et al (98) investigated green tea polyphenols during tamoxifen therapy and found no significant changes in the area under the plasma concentration-time curve (AUC) of endoxifen, which reflects overall systemic exposure, or in the maximum plasma concentration (Cmax) and trough plasma concentration (Ctrough) of endoxifen. Although polyphenols are often regarded as low-toxicity natural compounds, their clinical use as adjuncts to BC therapy requires caution. Some polyphenols and plant-derived compounds can modulate cytochrome P 450 (CYP) enzymes and drug transporters, thereby altering the pharmacokinetics of anticancer agents. A clinical case report described moderate neutropenia in a patient with BC receiving ribociclib and letrozole after self-administration of a supplement containing diosmin, escin and resveratrol, suggesting a possible CYP3A4-mediated interaction (99). Conversely, CYP3A4 induction by St. John's Wort may reduce exposure to drugs such as PTX and potentially compromise treatment efficacy. Therefore, the use of polyphenol-containing supplements during BC therapy should be evaluated on a case-by-case basis, especially for agents metabolized by CYP3A4 or drugs with narrow therapeutic windows.

Beyond direct antitumor effects, polyphenols have also been explored as supportive interventions for managing treatment-related toxicities in patients with BC. Lustberg et al (100) evaluated nanoemulsion curcumin in postmenopausal patients with BC with aromatase inhibitor-induced arthropathy. Although patient-reported outcomes and grip strength did not differ significantly between groups, the intervention showed good feasibility and adherence, and plasma curcumin was detectable only in patients receiving nanoemulsion curcumin. These findings suggest that nanoemulsion curcumin is clinically feasible, although its symptomatic efficacy requires further validation. Erfanian et al (101) investigated silymarin, a polyphenolic flavonolignan mixture from milk thistle, in patients receiving chemotherapy. The trial suggested potential hepatoprotective effects, particularly on alkaline phosphatase and bilirubin levels, while renal markers were not significantly improved. Another randomized controlled trial evaluated oral silymarin in patients with non-metastatic BC receiving doxorubicin-containing chemotherapy. Silymarin at 420 mg/day for 63 days helped prevent chemotherapy-related hepatotoxicity, mainly based on liver ultrasonography (102). These findings support the potential role of polyphenols in supportive care for patients with BC, particularly in reducing treatment-related organ toxicity. However, the current clinical evidence remains limited and larger randomized trials are needed to clarify optimal dosing, formulation, safety and clinically meaningful benefits.

Skin toxicity is a common supportive-care concern in patients with BC receiving radiotherapy or chemotherapy, with manifestations such as radiodermatitis, erythema, pain, desquamation and hand-foot syndrome. Therefore, several clinical studies have evaluated polyphenol-based interventions as adjunctive approaches to mitigate treatment-related skin toxicity, although their efficacy remains inconsistent. Ryan Wolf et al (103) evaluated topical curcumin gel for preventing radiation dermatitis and pain in patients with BC undergoing radiotherapy. Overall, curcumin did not significantly reduce dermatitis severity compared with placebo. However, exploratory subgroup analysis suggested potential benefit in patients with greater breast separation, indicating that curcumin-based supportive care may require risk-stratified patient selection. Another clinical trial further tested whether anthocyanins could protect against radiotherapy-induced skin toxicity in patients with BC (104). In this randomized, double-blind trial, oral anthocyanin supplementation did not improve skin elasticity, erythema, melanin changes or clinical toxicity scores compared with placebo. Heydari et al (105) evaluated topical curcumin for preventing radiation-induced dermatitis in patients with BC receiving radiotherapy. Compared with placebo, curcumin gel reduced redness and irritation during treatment and improved pain-related outcomes.

Taken together, current clinical evidence suggests that polyphenols may have translational value in BC management, particularly as adjuvant or supportive-care agents rather than as independent anticancer therapies. However, the available findings remain inconsistent and are limited by small sample sizes, heterogeneous formulations and doses, variable bioavailability, diverse treatment regimens and insufficient pharmacokinetic evaluation. Furthermore, potential herb-drug interactions should not be overlooked, especially in patients receiving chemotherapy, endocrine therapy, CDK4/6 inhibitors or other agents metabolized through CYP enzymes and drug transporters. Future well-designed multicenter, randomized, placebo-controlled trials are needed to clarify which polyphenols, formulations, doses and patient populations are most likely to achieve clinically meaningful benefits. Thus, while polyphenols represent a promising area for BC translational research, their clinical application should be approached cautiously, evidence-based and integrated with standard oncological care.