Role of flavonoids in inhibiting triple-negative breast cancer

Increasing incidences of metastasis or recurrence (or both) in triple-negative breast cancer (TNBC) are a growing concern worldwide, as these events are intricately linked to higher mortality rates in patients with advanced breast cancer. Flavonoids possess several pharmaceutical advantages with multi-level, multi-target, and coordinated intervention abilities for treating TNBC, making them viable for preventing tumor growth and TNBC metastasis. This review focused on the primary mechanisms by which flavonoids from traditional Chinese medicine extracts inhibit TNBC, including apoptosis, blocking of cell cycle and movement, regulation of extracellular matrix degradation, promotion of anti-angiogenesis, inhibition of aerobic glycolysis, and improvement in tumor microenvironment. This review aims to improve the knowledge of flavonoids as a promising pharmacological intervention for patients with TNBC.


Introduction
Approximately 13% of women globally are diagnosed with breast cancer (Giaquinto et al., 2022).Triple-negative breast cancer (TNBC) is a kind of cancer where the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER-2) are not expressed.TNBC exhibits a low differentiation rate, high invasiveness, and high metastasis and recurrence (Lu et al., 2023).This type of breast cancer makes up 12% of all cases in the US and has a 5-year survival rate that varies from 8% to 16% (Howard and Olopade, 2021).The treatment options for TNBC include surgical intervention, radiation therapy, chemotherapy, targeted therapy, and immunotherapy.However, limited therapeutic strategies for TNBC due to a lack of effective biological targets and biomarkers, diverse molecular subtypes, and complex biological behaviors and clinical characteristics have made it a significant clinical challenge for years.Therefore, developing more efficient therapeutic drugs is necessary.
Flavonoids derived from TCM exhibit a diverse array of anti-tumor properties that can be combined with modern therapies to improve treatment efficacy and prevent the occurrence of breast cancer.Flavonoids extracted from TCM have wide-ranging effects linked to multiple cancer-related signaling pathways.This review briefly introduces flavonoids from TCM extracts, their targets, and potential mechanisms for TNBC.

Molecular pathogenesis of breast cancer 2.1 Breast cancer cell apoptosis
A disequilibrium between cellular division and cell death leads to uncontrolled proliferation of cancer cells.Apoptotic signaling pathways can be categorized into three distinct types: intrinsic, extrinsic, and endoplasmic reticulum pathways.Apoptosis evasion mechanisms can be roughly classified into three types: diminished caspase function, impaired death receptor signaling, and an altered balance of pro-apoptotic and anti-apoptotic proteins.This is related to the disruptions in the equilibrium of the Bcl-2 family, defects in the p53 tumor suppressor gene, anomalous expression of apoptosis protein inhibitors, decreased caspase activity, and impaired death receptor signaling (Singh and Lim, 2022).

Cell cycle arrest
Cell cycle dysregulation is the basis of uncontrolled cell proliferation.Cells that have lost the checkpoint mechanisms have highly unstable genomes.In breast cancer, cell cycle abnormalities are frequently observed, including the loss of Rb function, inhibitors, and increased abundance of cyclin D, cyclin E, and cyclin-dependent kinase (CDK).Cyclin D1 controls how cells move from the G1 phase, where they prepare for DNA replication, to the phase where they actually copy their DNA.This gene is also important for preventing human breast cancer cells from growing too much.There is a strong correlation between the elevated expression of CCND1, which codes for the protein Cyclin D1, and decreased survival rates (Aftab et al., 2021).Cyclin E serves as a potent prognostic indicator of breast cancer and plays a crucial role in determining tumor aggressiveness and predicting the recurrence of TNBC (Guerrero Llobet et al., 2020).

Regulation of extracellular matrix degradation
Breast cancer cells become potentially malignant after penetrating and dissolving the extracellular matrix (ECM), particularly the basement membrane.Epigenetic mechanisms are important for regulating EMT/ECM-related pathways.When cancer cells acquire mesenchymal features, it promotes the advancement of TNBC, and the process of DNA methylation and the action of enzymes that modify histones contribute to changes in ECM/EMT alterations in TNBC (Zolota et al., 2021).Matrix metalloproteinases (MMPs) are proteolytic enzymes containing active Zn 2+ .MMP9 degrades the ECM near tumors, which are intimately associated with tumor invasion and metastasis, performs the final degradation of collagen fibers, and removes malignant cells from the complicated network around them.Collagen is a significant metabolite of connective tissue that undergoes a two-step degradation process in mammary gland tissue.MMP-2 and MMP-9 specifically target the breakdown of denatured interstitial collagen or gelatin, as well as collagen types IV and V found in the basement membrane.MMP-1 is the sole MMP enzyme that can degrade all types of collagen in the mammary gland and is crucial in breaking down stromal fibers in various diseases (Argote Camacho et al., 2021).MMP9 is crucial for the development of the "metastatic niche" and controls the spread of cancer cells to the lungs when overexpressed.The coexpression of MMP-1, MMP-2, and MMP-9 may indicate an unfavorable prognosis in patients with breast cancer (Mohammadian et al., 2020;Jiang and Li, 2021).

Inhibition of the epithelial-mesenchymal transition (EMT)
Epithelial-mesenchymal transition (EMT) is a significant process that triggers tumor invasion and metastasis.Cancer metastasis can be divided into multiple phases, including in situ tumor growth, EMT, invasion, infiltration, survival in blood circulation, extravasation, dormancy, and metastatic growth (Fares et al., 2020).EMT involves the disruption of cell adhesions in cancer cells originating from epithelial tissue and the upregulation of particular metabolites in the constricted cytoskeleton, leading to a mesenchymal phenotype characterized by increased invasiveness and the migration of primary cancers.TNBC cells evolve from epithelial cells to hybrid epithelial/ mesenchymal (E/M) and strong mesenchymal patterns during invasion.Similarly, during colony formation, TNBC cells transition from epithelial cells to a hybrid E/M state (Grasset et al., 2022).EMT is commonly identified by loss of cytokeratin and E-cadherin and gain of mesenchymal-associated molecules, N-cadherin, fibronectin, and vimentin.EMT involves many signaling pathways, including NF-κB, TGF-β, Akt, Wnt, Notch, PPARγ, and RAS, and is also affected by hypoxia and microRNA (miRNA) expression.The transcription factors TWIST, Snail, and Zeb1/Zeb2, as well as epigenetic regulators, miRNAs, and alternative splicing, are regulated by these signaling pathways during breast cancer growth.

Breast cancer stem cells
Breast cancer stem cells (BCSCs) are stem cells within a tumor that possess the ability to regenerate themselves and have the potential to develop into malignancies.The variation in tumors among different individuals can be ascribed to the inherent molecular subtypes of breast cancer, while the variation within a tumor can be elucidated by the concept of cancer stem cells, which primarily infiltrate the adjacent mesenchyme or enter the circulatory system through EMT during tumor metastasis.BCSCs undergo a mesenchymal-epithelial transition (MET) to form massive metastatic colonies in distant organs (Lu and Kang, 2019).BCSCs show higher metastatic potential due to the upregulation of proteins associated with cell metastasis and motility, as well as the downregulation of adhesion proteins.Tumorigenicity is demonstrated by the activation of many pathways associated with BCSCs.Furthermore, The ability of BCSCs to easily transition between EMT and MET is essential for promoting both EMT and metastasis in breast cancer.In addition, immunosuppressive cells are recruited by BCSCs to promote breast cancer progression.
BCSCs maintain quiescent to prevent elimination by immune cells that are effective in their function, or they can establish a microenvironment that suppresses the immune system by attracting populations that inhibit immune detection (Tallerico et al., 2017).BCSCs of NTBC can be identified using specific markers, such as CD44, CD24, CD133, and aldehyde dehydrogenase (Brugnoli et al., 2019).They are also influenced by various signaling pathways, such as BMP2, Wnt, NF-κB, Notch, STAT3, and Hedgehog, which regulate their growth, survival, and migration.

Anti-angiogenesis
Angiogenesis provides nourishment and oxygen to tumor tissue and disseminates cancer cells via blood vessels.Tumor blood vessels exhibit structural instability and dysfunction, leading to inflammation and tissue fibrosis, DNA hypermethylation, genomic instability, transdifferentiation, immunosuppression, growth, invasion of tumor cells, and resistance to apoptosis (Martin et al., 2019).Stagnation of blood flow results in reduced vascular permeability and blood concentration, thereby reducing the pH in tissues and inducing hypoxia.Activated hypoxia-inducible transcription factors (HIFs) stimulate angiogenesis, leading to higher invasiveness and/or resistance to treatment (Kao et al., 2023).Furthermore, due to the widespread occurrence of vascular leakage in tumors, tumor cells invade the systemic circulation, leading to metastasis (Tomita et al., 2021).The dysregulation of tumor-associated angiogenesis is controlled by diverse molecular elements, including vascular endothelial growth factor (VEGF), TGF-β-1, Interleukin (IL)-8, CD34, CD31, Factor VIII, angiopoietin-1, angiopoietin-2, platelet-derived growth factor, and fibroblast growth factor (FGF)-2.

Suppression of aerobic glycolysis
Abnormal metabolism is one of the most significant characteristics of malignancy.The Warburg effect, a feature of cancer cell energy metabolism, refers to the ability of tumor cells to utilize glycolytic products to synthesize their growth requirements under normoxic or hypoxic conditions.Despite the presence of sufficient oxygen, most tumor cells, including those in breast cancer, produce a substantial amount of energy through hyperglycolytic metabolism.Aerobic glycolysis closely regulates the proliferation and survival of breast cancer cells.Elevated levels of aerobic glycolysis hinder the effectiveness of cancer treatment and promote resistance to therapeutic agents.Aerobic glycolysis is assessed using fluorodeoxyglucose positron emission tomography (FDG-PET) and is used to monitor cancer recurrence and metastasis.The aerobic glycolytic pathway involves several key enzymes, such as hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase, and glucose transporters.TNBC has distinct hypoxic characteristics and demonstrates abundant expression of HIF-1α (Liu et al., 2022).Other signaling pathways such as PI3K/ Akt, mammalian target of rapamycin (mTOR), and AMP-activated protein kinase, along with transcription factors such as c-Myc, p53, and HIF-1 are also overexpressed in TNBC.

Tumor-associated macrophages
Tumor-associated macrophages (TAMs) are the primary immune cells in the microenvironment of breast tumors.These macrophages enhance the growth of breast tumors by inducing breast cancer stemness, controlling energy metabolism, stimulating angiogenesis, drug resistance and cancer cell metastasis, and supporting immune system suppression (Munir et al., 2021).These mechanisms include the secretion of inhibitory cytokines, promotion of regulatory T cells (Tregs), and reduction of effector functions of tumor-infiltrating lymphocytes.TAMs regulate PD-1/ PD-L1 expression.TAMs demonstrate a significant level of cellular plasticity, and changes in the TME lead to the transformation of TAMs into M1 macrophages, which mediate anti-tumor immune responses (Huang et al., 2022).TNBC induces M2 macrophage polarization, which positively feedback promotes the malignant evolution of TNBC cells.M2 promotes the migration of TNBC cells and induces angiogenesis in TNBC.Reversing M2 polarization is considered a target for cancer treatment (Meng et al., 2022).

Chemokines
The TME comprises a heterogeneous combination of immune cells and soluble mediators, including chemokines, cytokines, and growth factors.These metabolites are found within or close to tumors.Chemokines function as immunological mediators, attracting and recruiting particular subsets of these cells into the TME and promoting tumor growth or regression.Some chemokines, such as CXCL9, CXCL10, and CCL16, can inhibit the growth of breast cancer cells.Other chemokines, such as CCL2, CCL5, CXCL8, and CXCL12, promote the growth of breast cancer (Masih et al., 2022).

Bone microenvironment
In the bone microenvironment, diverse cell types, including osteocytes, adipocytes, endothelial cells, and neural cells, are essential in maintaining bone homeostasis.The development of bone metastases is a selective and multistep process.The growth, dormancy, and metastasis in the bone microenvironment linked to breast cancer are influenced by various bone marrow environments, including the endosteal (comprising osteoblasts, osteoclasts, and adipocytes) and vascular niches.After tumor cells invade the bone, they rely on stromal cells to further their survival and proliferation.Therefore, the intricate equilibrium between bone resorption and generation is disturbed.Osteolytic lesions constitute most breast cancer metastases.Bone metastases from breast cancer are characterized by osteoclastic bone resorption.Osteoclasts modulate bone resorption and promote the activation of malignancy cells (Zarrer et al., 2020).

Hormones
Phytoestrogen are subtype of flavonoids and can mimic or induce estrogen-like responses.Their hydroxyl groups and phenolic rings, which are necessary for binding ERα and ERβ, make them similar to the most significant form of E2.Thus, ER, ERα, and ERβ can interact with the bioavailable phytoestrogens.In breast tissue, ERα activation promotes cell proliferation while ERβ decreases it and promotes apoptosis.In TNBC, the effects triggered by E2 are not only conducive to tumor growth but can also have anti-tumor properties, such as through the activation of ERβ.Decreased expression of mitochondrial ERβ led to a decline in mitochondrial activity in TNBC cells, promoting their growth through glycolysis and contributing to tumor advancement.Conversely, the enforced overexpression of mitochondrial ERβ reduced the proliferation of TNBC cells (Song et al., 2019).ERβ suppresses the growth of TNBC cell lines and also hinders their involvement in the formation of new blood vessels, invasion, and spread to other parts of the body.The ER-Beta agonist S-equol can effectively suppress the growth of TNBC by reducing the levels of Ki-67 (Lathrop et al., 2020).Chronic stress can contribute to the development of cancer.One of the most significant mechanisms is the continuous release of neurotransmitters caused by chronic stress, which ultimately leads to the activation of β2-adrenergic receptors (β2-AR) (Bernabé, 2021).

Drug resistance
Standard chemotherapy remains the cornerstone of systemic therapy, but TNBC often becomes resistant to cytotoxic drugs (Ou et al., 2024).According to the National Comprehensive Cancer Network guidelines, anthracyclines, taxanes, anti-metabolites, and microtubule inhibitors are preferred for chemotherapy.TNBC drug resistance mechanisms include antioxidant activity, mediation of drug efflux, reduction of intracellular drug accumulation, mediation of intracellular detoxification of cytotoxic drugs, enhanced DNA repair, anti-apoptosis, anti-autophagy, metabolic reprogramming, EMT, TME heterogeneity, and immune evasion (Bai et al., 2021).One potential approach to enhance the effectiveness of therapies and minimize their adverse effects involves reversing medication resistance and enhancing sensitivity to chemotherapy.Therefore, it is crucial to choose medications that are less toxic and more effective for patients with cancer.Therefore, flavonoids have been investigated as potent chemosensitizers in conjunction with standard chemotherapeutic drugs.

Flavonoid
As shown in Figure 1, there are many therapeutic targets that show potential clinical utility in the treatment of TNBC.The following will introduce the inhibitory effects of specific drugs on TNBC. Figure 2 shows chemical structure of flavonoids.Tables 1, 2 provide a concise overview of the pertinent research findings from both in vivo and in vitro trials on various medications.Figure 3 summarizes the relevant pathways.
Luteolin suppresses TNBC by inducing apoptosis and autophagy through the SGK1-FOXO3a-BNIP3 signaling pathway (Wu et al., 2023).AKT/mTOR-inducing H3K27Ac and H3K56Ac levels were decreased by luteolin, which in turn controlled MMP9 production, thereby suppressing the growth and metastasis of TNBC via the androgen receptors (Wu et al., 2021).Luteolin inhibits YAP/TAZ activity, suppressing EMT and the migration of TNBC (Cao et al., 2020), effectively inhibiting TNBC metastasis by reversing EMT through the suppression of β-catenin (Lin et al., 2017).Luteolin effectively reduced the characteristic features of breast cancer stemness by inhibiting the expressions regulated by Nrf2 (Tsai et al., 2021).Furthermore, luteolin inhibited the metastasis of MDA-MB-435 and MDA231-LM2-4175 cells to the lungs in vivo, and its capacity to prevent the generation of VEGF and block kinase domain receptor-mediated activity may contribute to its anti-metastatic effects (Cook et al., 2016).Luteolin effectively suppresses Notch signaling by modulating specific miRNAs involved in tumor growth.These include upregulated miR-34a, miR-139-5p, miR-181a, miR-224, and miR-246, and downregulated miR-155 (Sun et al., 2015).The anti-tumor effects of luteolin on TNBC cell growth and EMT may be attributed to the inhibition of Ras/Raf/MEK/ERK signaling, which is suppressed by miR-203 (Gao et al., 2019).
In TNBC, Quercetin suppresses breast cancer cell growth and survival by targeting the Akt/mTOR/PTEN signaling pathway (Jiang et al., 2024).Quercetin alters FOXO3a signaling and causes apoptosis and cell cycle arrest (Nguyen et al., 2017).By suppressing fatty acid synthase and β-catenin, quercetin induces apoptosis in TNBC cells (Sultan et al., 2017).Quercetin inhibits the progression and migration of TNBC cells by impairing HuR activity (Umar et al., 2022).Quercetin induces EMT by influencing the positioning of β-catenin within the cell nucleus and controlling the expression of genes targeted by β-catenin (Srinivasan et al., 2016).Quercetin controls the β-catenin signaling pathway and decreases the movement of TNBC cells.Quercetin hampers the growth of tumors, suppresses oncocytes proliferation, and induces tumor necrosis.Furthermore, it also inhibits cancer cell migration by suppressing glycolysis through the induction of autophagy mediated by the Akt-mTOR pathway (Jia et al., 2018).Quercetin inhibits the growth of human breast cancer cells by increasing miR-146a expression, followed by the induction of apoptosis via cystatinase-3 activation and the mitochondria-dependent pathway and inhibition of invasion via downregulation of epidermal growth factor receptor (EGFR) expression (Tao et al., 2015).Quercetin could inhibit chronic stress-induced ERK1/ 2 activity in TNBC cells, thereby weakening the potential for TNBC growth and metastasis (Zhang J. et al., 2024).Quercetin boosts the efficiency of doxorubicin in treating human breast cancer cells while minimizing its harmful side effects.This is achieved by decreasing the expression of efflux ABC transporters (Li S. et al., 2018).The efficacy of sorafenib is improved by quercetin, which reduces the levels of two drug efflux transporters: P-glycoprotein and BCRP (Louisa and Wardhani, 2019).Quercetin reduces the harmful effects of doxorubicin-cyclophosphamide treatment on the heart, enhancing its ability to treat TNBC.Quercetin may reduce the harmful effects of AC-induced heart damage by preventing the buildup of ROS and stimulating the ERK1/2 pathway in heart muscle cells.Thus, quercetin may augment the anti-cancer efficacy of AC by suppressing ROS accumulation and inhibiting the ERK1/ 2 pathway in TNBC cells (Zhang et al., 2022).Quercetin reverses talazopanib resistance in BRCA1-mutated TNBC cells by improving cytotoxicity and apoptosis (Eskiler et al., 2020).By modulating the IL-6/JAK2/STAT3 signaling pathway, quercetin reduces the number of Treg cells and activates the anti-tumor immune response (Liao et al., 2024).Cyclophosphamide and quercetin increased the overall occurrence of T cells and NK cells in the body, while decreasing the occurrence of Treg cells, which are associated with suppressing tumour growth (Manni et al., 2023).and Pinellia ternata (Thunb.)Makino [Araceae] has diverse effects, including anti-cancer, anti-inflammatory, anti-apoptotic, and antibacterial properties (Bajek-Bil et al., 2023).The IC50 values of baicalein in MDA-MB-231 cells were 60.12 μM at 24 h, 27.98 μM at 48 h, and 19.01 μM at 72 h.Baicalin suppresses tumor growth in MDA-MB-231 cells by decreasing the expression of MMP-2, MMP-9, uPAR, and uPA by disrupting the p38MAPK signaling pathway (Wang X.-F. et al., 2013).Furthermore, baicalin targets β-catenin signaling to reverse EMT, thereby inhibiting the metastasis of breast cancer cells (Zhou et al., 2017).Baicalin substantially inhibited the proliferation of bone metastases, reduced bone degradation, diminished osteoclastogenesis of osteoclast progenitors, and inhibited the growth of metastasized MDA-MB-231 cells, thus maintaining bone mass (Wang B. et al., 2020).Baicalin reduces the viability, motility, and invasion of breast cancer cells by modulating MORC4 and miR-338-3p (Wang B. et al., 2020).Baicalin notably reduces breast cancer cell survivability, mobility, and invasiveness by controlling the TGF-β/ lncRNA-MALAT1/miR-200c pathway (Li et al., 2022).Furthermore, Baicalein triggered programmed cell death and self-degradation in triple-negative breast cancer cells by blocking the PI3K/AKT pathway (Yan et al., 2018).Baicalein suppressed fibronectin-induced EMT by reducing calpain-2 activation and upregulation (Chen et al., 2019).Baicalein inhibited EMT in breast cancer by regulating the polarization of TAMs (Zhao et al., 2018).Baicalein may inhibit EMT, which is linked to the downregulation of the Wnt/β-catenin pathway and SATB1 to decrease breast cancer metastasis (Ma et al., 2016).By blocking the G-protein-coupled receptor 30 pathway, baicalein prevents 17-β-estradiol from causing BC cells to migrate, adhere, or invade (Shang et al., 2015).Baicalein decreased CDK1 activity through autophagy, increasing MDA-MB-231 cells' susceptibility to doxorubicin (Hua et al., 2023).

Daidzein
Daidzein, an isoflavone, possesses significant nutritional value and is primarily derived from soy plants Cyathula officinalis K.C.Kuan [Amaranthaceae] and Corethrodendron multijugum (Maxim.)B.H. Choi and H.Ohashi [Fabaceae], and Spatholobus suberectus Dunn [Fabaceae].Daidzein has biphasic effects on breast cancer cell proliferation and ERα expression, with either stimulatory or inhibitory effects.It exhibits pharmacological and therapeutic characteristics, including cholesterol-lowering, cardiovascular function improvement, anti-tumor, anti-fibrotic, and anti-diabetic properties (Ubaid et al., 2023).Daidzein's anticancer properties in TNBC involve inducing cell cycle arrest, particularly at the G1 and G2/M phases (Choi and Kim, 2008).
Rutin efficiently arrests the cell cycle in chemoresistant TNBC cells by inhibiting P-gp and BCRP pumps, reversing multidrug resistance, and restoring sensitivity to cyclophosphamide (Iriti et al., 2017).
[Berberidaceae] has various beneficial properties, including anti-inflammatory, antioxidant, antidepressant, and aphrodisiac effects (Liu et al., 2023).Icariin triggers autophagy to hinder the progression of TNBC by stimulating the AMPK/mTOR/ULK1 signaling pathway (Zhao et al., 2024).By altering the lncRNA NEAT1/TGFβ/ SMAD2 Signaling Pathway, Icariin regulates EMT and stem celllike characteristics in breast cancer (Song et al., 2024).Icariin triggered cellular apoptosis and broke the positive regulatory loop between ER-α36 and EGFR in TNBC cells, resulting in a reduction of cell growth promoted by E2 in TNBC et al., 2017).It induces apoptosis by increasing ROS levels and suppressing the invasion of TNBC cells through the JNK/c-Jun signaling channel (Gao et al., 2023).Icariin induces apoptosis and inhibits migration of TNBC through the SIRT6/NF-κB signaling pathway.Icariin exhibits tumor growth inhibition and anti-lung metastasis effects in tumor animal models of MDA-MB-231 and 4T1 cells via the immunosuppressive microenvironment of the tumor (Song et al., 2020).Frontiers in Pharmacology frontiersin.org11 several other sources.It possesses notable antibacterial, antifungal, anticancer, antioxidant, antiprotozoal, and anti-inflammatory properties (Periferakis et al., 2022).Low-dose kaempferol inhibited TNBC cell migration and encroachment by plugging the RhoA and Rac1 signaling channels, whereas HER2 overexpression rescued both cell migration and RhoA and Rac1 activation in kaempferol-treated MDA-MB-231 cells (Li et al., 2017).The combined anticancer effect of kaempferol and verapamil is strengthened by deregulation the CD44-NANOG-MDR1-associated chemoresistance pathway in breast cancer stem cells (Nandi et al., 2022).

Nobiletin
Nobiletin, a flavonoid extracted from Citrus reticulata Blanco [Rutaceae], exhibits many positive effects, including neuroprotection, cardiovascular protection, anti-metabolic disorder prevention, anticancer, anti-inflammatory, and antioxidant properties (Arshad et al., 2024).Nobiletin induces apoptosis and pyroptosis of TNBC cells via miR-200b/JAZF1/NF-κB axis (Wang et al., 2021).Nobiletin exhibits anti-cancer effects in TNBC cells via inducing apoptosis through Bcl-xL and causing cell cycle arrest in the G0/G1 phase (Chen et al., 2014).The anti-cancer effectiveness was improved by activating retinoic acid receptor-related orphan receptors with nobiletin.This enhancement is achieved by suppressing the IκB/NF-κB signaling pathway in TNBC.Signal pathway related to flavonoids inhibiting triple negative breast cancer.
Frontiers in Pharmacology frontiersin.org The concurrent use of nobiletin with either docetaxel or carboplatin effectively suppresses the proliferation of TNBC cells (Kim et al., 2022).

Genistein
Genistein is a prevalent isoflavone present in soy products.Genistein demonstrates anti-inflammatory, antioxidant, antibacterial, and antiviral properties.It impacts angiogenesis and estrogen synthesis and has pharmacological effects on diabetes and lipid metabolism (Sharifi-Rad et al., 2021).Eisenstein effectively attenuated complications in TNBC lacking ERs across all doses (Malik et al., 2023).Genistein suppresses the growth of TNBC cells by reducing the activity of NF-κB through the Notch-1 pathway (Pan et al., 2012).Genistein can effectively suppress the growth of TNBC cells by intricately modulating the cell cycle and the response to DNA damage (Fang et al., 2016).Genistein can potentially prevent and reverse AHR-dependent BRCA1 hypermethylation and restore ERα-mediated responsiveness.This makes TNBC more sensitive to estrogen therapy (Donovan et al., 2019).

Apigenin
Apigenin is found in several medicinal plants, such as Plantago indica L. [Plantaginaceae] and Lobelia chinensis Lour.[Campanulaceae], and Mentha canadensis L. [Lamiaceae].Apigenin exhibits anti-tumor, cardioprotective, neuroprotective, and anti-inflammatory effects (Salehi et al., 2019).The IC50 values of apigenin in MDA-MB-231 and MDA-MB-436 cells were around 33 and 30 μM, respectively, after 72 h.Apigenin alters transcriptome-wide TNBC-specific alternative splicing, specifically in TNBC, leading to apoptosis and tumor growth inhibition (Sudhakaran et al., 2023).Apigenin inhibited the invasion of xenograft tumors derived from MDA-MB-231 by decreasing the IL-6-associated downstream signaling cascade (Lee H. H. et al., 2019).Apigenin inhibits the activation of the PI3K/Akt channels and the activity of integrin β4, resulting in a decrease in the metastasis of tumor cells to the lungs in nude mice and the occurrence of spontaneous intravasation and organ metastasis in chick embryos (Lee et al., 2008).Apigenin inhibits YAP/ TAZ activity in TNBC cells and suppresses the stem cell-like properties of apigenin in TNBC cells, which is partially mediated by disturbing the YAP/TAZ-TEAD protein-protein interaction (Li Y.-W. et al., 2018).By concentrating on hnRNPA2, apigenin modulated the activity of ABCC4 and ABCG2 drug expulsion transporters and increased the sensitivity of TNBC spheroids to DOX-induced apoptosis (Sudhakaran et al., 2020).Apigenin boosts the suppressive impact of cisplatin on telomerase activity in TNBC cells (A.Aziz et al., 2017).Apigenin may induce apoptosis in breast cancer cells by activating the PI3K/AKT/ Nrf2 pathway.Additionally, it can enhance the tumor immune microenvironment in mice with breast tumors, leading to the suppression of breast cancer growth (Zhang C. et al., 2024).

Maackiain
Maackiain is a flavonoid with several functions and is extracted from many Chinese herbs, including Spatholobus suberectus Dunn [Fabaceae] and Sophora flavescens Aiton [Fabaceae].Maackiain exhibits many pharmacologic activities, including anti-cancer, anti-allergic, and anti-inflammatory effects (Huh et al., 2020).Maackiain regulates the miR-374a/GADD45A axis to suppress the beginning and marching of TNBC (Peng et al., 2022).

Baohuoside I
Baohuoside I (BHS) is a flavonoid derived from the plant Epimedium sagittatum (Siebold and Zucc.)Maxim.
[Berberidaceae] and has several pharmacological activities, including anti-osteoporotic and anti-tumor effects, enhancement of cognitive function, protection against cerebral ischemiareperfusion injury, and neuroprotection (Agrawal et al., 2024).BHS effectively inhibits breast cancer metastasis and the activation of TAMs/CXCL1 in mouse breast cancer xenografts as well as in a zebrafish model of breast cancer xenotransplantation (Wang S. et al., 2020).

Isoliquiritigenin
Isoliquiritigenin, a flavonoid obtained from the plant Glycyrrhiza glabra L. [Fabaceae], has many pharmacological properties such as anticancer, antiaging, antioxidative, antiinflammatory, and anti-diabetic effects (Zhao et al., 2019).Isoliquiritigenin efficiently suppress the growth of TNBC cells by inducing apoptotic cell death and promoting the accumulation of p62, which in turn stimulated autophagy-mediated apoptosis (Lin et al., 2020).Isoliquiritigenin suppresses the formation of new blood vessels in TNBC by targeting the VEGF/VEGFR-2 signaling pathway (Wang Z. et al., 2013).Isoliquiritigenin has the ability to regulate the miR-374a/PTEN/Akt pathway, which leads to the inhibition of breast cancer tumor growth and spread (Peng et al., 2017).Isoliquiritigenin derivative also had a more significant inhibitory effect on breast cancer cell viability, especially on MDA-MB-231 (Peng et al., 2020).

Conclusion
Treating TNBC is challenging because it has few effective therapeutic options.Recent studies have shown the anti-tumor properties of several natural metabolites, including flavonoids.There are many types of flavonoids, and how to screen and summarize the most effective ingredients from a large number of compounds remains a challenge.In addition, although the research on flavonoids has made certain progress, there is still a lack of a mature and unified framework to guide its application in clinical treatment.In this case, the concept of holism and treatment based on pattern differentiation of traditional Chinese medicine provide a new direction to explore the potential of flavonoids in tumor treatment.Based on the investigation of literature and ancient books, starting from ethnic folk medicines, clinical prescriptions and experience prescriptions, the selection is made with reference to the medicinal properties and efficacy of the drugs.The medicinal properties represented by the four qi and five flavors, meridians, ascending and descending, floating and sinking, etc., are theories for studying the properties and application rules of traditional Chinese medicine.Linking the efficacy of drugs with modern pharmacological mechanisms is the focus of future research.Various traditional Chinese medicines with functions such as nourishing the body and eliminating evil, clearing heat and detoxifying, promoting blood circulation and removing blood stasis have been proven to have direct or indirect anti-tumor effects.
This review provides a thorough overview of the various mechanisms by which flavonoids can effectively treat TNBC, including regulating cell proliferation and cell cycle, inhibiting cell invasion and metastasis, overcoming drug resistance, inducing apoptosis and autophagy, and inhibiting angiogenesis.Additionally, this review delves into the specific effects of different flavonoid metabolites or treating TNBC.Flavonoids are natural substances with anti-cancer activities.When combined with TCM, they can improve their efficacy and treatment outcomes.However, the bioavailability of flavonoids is low, their dosage is difficult to control, and are also potentially toxic.It is challenging to find definitive and universally applicable mechanisms of action in mechanism research.The structure-activity relationship should be conducted to design and optimize compounds.Clinical and basic research need to be closely integrated and verified to ensure clinical safety and effectiveness.The anti-cancer properties of flavonoids have opened new avenues for pharmacological intervention in TNBC.

FIGURE 1
FIGURE 1Molecular pathogenesis of breast cancer.
Kaempferol is found in high levels in tea, Paeonia lactiflora Pall [Paeoniaceae], Platycladus orientalis (L.) Franco [Cupressaceae] and Morin, a widely recognized flavonoid derived from plants in the Moraceae family and the leaves of Maclura tricuspidata Carrière [Moraceae], has anti-inflammatory, anti-oxidant, anti-diabetic, antitumor, anti-hypertensive, antibacterial, and neuroprotective properties (Maharjan et al., 2021).MDA-MB-231 cell death triggered by morin results from prolonged interruption of the cell cycle, which occurs due to the activation of ERK and suppression of FOXM1 signaling pathways, leading to the stimulation of p21 expression.Morin suppresses FOXM1 and attenuates EGFR/STAT3 signaling pathways to sensitize TNBC cells to doxorubicin cytotoxicity (Maharjan et al., 2023).

TABLE 1 (
Continued)In vitro study on the inhibition of triple-negative breast cancer by flavonoids.

TABLE 1 (
Continued)In vitro study on the inhibition of triple-negative breast cancer by flavonoids.

TABLE 2
In vivo study on the inhibition of triple-negative breast cancer by flavonoids.

TABLE 2 (
Continued)In vivo study on the inhibition of triple-negative breast cancer by flavonoids.