Targeting Molecular Pathways in Breast Cancer Using Plant-Derived Bioactive Compounds: A Comprehensive Review

Introduction

Breast cancer remains one of the most prevalent and challenging malignancies worldwide, with significant morbidity and mortality among women in 2022, there were approximately 2.3 million new breast cancer cases and 670,000 deaths.¹ According to GLOBOCAN (2021), in 2020, the number of new breast cancer cases in Indonesia reached 68,858, accounting for 16.6% of the total 396,914 new cases, with the death toll exceeding 22,000 cases.^2–4Breast cancer arises due to a combination of internal and external factors.^5–7Breast cancer arises from genetic mutations in key tumor suppressor genes such as BRCA1, BRCA2, and TP53, resulting in uncontrolled cellular proliferation, resistance to apoptosis, and genomic instability. Several signalling pathways are implicated in breast cancer progression, including EGFR, RAF/MEK/ERK, NF-κB, JAK-STAT3, BCL-2, p53, and SKP/p21, each of which regulates critical cellular processes such as growth, differentiation, and metastasis. Research also indicates that poor lifestyle habits, environmental exposures, and socio-psychological influences contribute to its development.^8,9 Approximately 5% to 10% of breast cancer cases are linked to genetic mutations and family history, while 20% to 30% can be attributed to modifiable risk factors.¹⁰

Figure 1 A search strategy flow diagram.

Conventional treatments, including surgery, chemotherapy, radiation, and hormone therapy, have improved survival rates but are often accompanied by severe side effects and limitations.^11,12 Consequently, there is an increasing interest in exploring alternative and complementary therapies that are both effective and less harmful.¹³ Among these, natural compounds derived from plants have garnered substantial attention due to their bioactive properties and potential anti-cancer activities.^14,15 Plants provide a rich source of bioactive compounds such as flavonoids, alkaloids, terpenoids, and phenolics, which have shown promise in fighting cancer by triggering apoptosis, slowing cell proliferation, and inhibiting angiogenesis and metastasis.^16–18Their ability to target multiple pathways makes them valuable in cancer treatment.¹⁹ Research on plant-derived compounds includes in vitro, in silico, and in vivo studies. In silico methods use computational techniques to predict how these compounds interact with cancer-related targets, optimizing their structures and assessing pharmacokinetics.^20–22 In vitro studies test their effects on cancer cells, evaluating cytotoxicity, apoptosis, and cell cycle impact.^23,24 In vivo studies conducted on animal models help determine their effectiveness, safety, and bioavailability, bridging the gap to clinical application.^24–26

However, the safety profiles of many plant-derived agents remain under-characterized, with limited data on their potential off-target toxicity and optimal dosing parameters.^27,28 In contrast, conventional cancer therapies possess well-defined therapeutic insights and dosing guidelines, underscoring the need for comprehensive toxicity and pharmacokinetic studies of novel botanical candidates prior to clinical application.^29,30 The safety profiles of many plant-derived agents remain under-characterized, with scarce data on their off-target toxicity and safe dosing ranges. Without standardized toxicity testing (eg acute and sub-chronic LD₅₀ or NOAEL assays), the translational potential of crude extracts and fractions is difficult to assess^28,31.This gap underscores the need for comprehensive pharmacokinetic and toxicological evaluations prior to clinical application.

This review explores the potential of plant-based compounds in breast cancer treatment, summarizing key findings from different study approaches. By understanding their mechanisms, identifying promising candidates, and addressing challenges, we aim to contribute to developing effective, natural therapies that could improve patient outcomes and quality of life.

Materials and Methods

At the start, the reference was limited to published from 2014 to 2025. The search for papers was conducted using Scopus. The search technique employed synonyms and related concepts interchangeably as keywords. The Boolean operators “AND”, “AND NOT”, and “OR” were used to combine and exclude terms in the following way: (1) A search was performed in the Scopus database using the terms Breast cancer AND Herbal medication OR Plant extract OR natural Compound AND route OR Signalling pathway, AND NOT preclinical study OR Clinical trial. The search was restricted to the Article title, Abstract, and Keywords. The search yielded a total of 1034 articles. (2) All papers identified through these searches were subsequently assessed to ascertain whether they satisfied the review’s criteria for inclusion. Eligible studies were original, peer‐reviewed research articles published in English from 2014 onward that focused specifically on breast cancer and evaluated the molecular mechanisms of action of individual plant-derived compounds, whether by in silico modeling, in vitro assays, and in vivo experiments, within defined signaling pathways such as EGFR, PI3K/AKT/mTOR, or NF-κB. We excluded any publications before 2014, non-English articles, studies that did not address breast cancer, investigations of multi-component extracts or mixtures without isolating a single bioactive agent, reports lacking a clear examination of pathway-specific mechanisms, and non-original literature types such as reviews, editorials, conference abstracts, or commentaries (Figure 1).

Results

EGFR Pathway

The EGFR, or epidermal growth factor receptor, belongs to a family of receptor tyrosine kinases that also includes three other members (erbB2/HER-2, erbB3/HER-3, and erbB4/HER-4) [67]. The receptors are located within the cytoplasmic membrane and share a similar structure, including an extracellular domain that binds to ligands, a short hydrophobic region that crosses the membrane, and an intracellular domain with a tyrosine kinase.^32,33 EGFR is triggered through receptor overexpression, which is frequently observed in cancer. Furthermore, it can be activated through both ligand-dependent and ligand-independent pathways. Six known ligands can bind to the EGFR, including EGF and transforming growth factor-α. Upon ligand binding, EGFR undergoes dimerization and then phosphorylates particular tyrosine residues within its intracellular domain. This initiates a sequence of signaling cascades, which involve the RAS/RAF/MEK/ERK and PI3K/AKT pathways.³³ EGFR triggers the activation of the RAS/RAF/MEK/ERK pathway, leading to the phosphorylation of ERK.³⁴ Subsequently, ERK translocates to the nucleus and regulates gene expression associated with cell proliferation and survival. Concurrently, the initiation of the PI3K/AKT pathway results in the phosphorylation and stimulation of AKT, which enhances cell survival and growth by inhibiting programmed cell death and enhancing protein production via mTOR signaling.³⁵

Based on in silico assay, Terminalia chebula has shown promise in blocking the EGFR by directly binding to its active site, stabilizing it in an inactive state, and preventing downstream oncogenic signaling (Table 1). Saccharopine, a bioactive compound from Terminalia chebula, directly binds to EGFR (PDB ID: 3W2S) with a high binding affinity of −9.7 kcal/mol, which is stronger than the standard reference ligand 17β-estradiol (−4.4 kcal/mol). Molecular docking simulations showed that saccharopine interacts with key EGFR active site residues, including GLN-791, MET-793, CYS-797, THR-854, and ASP-855, stabilizing the receptor in an inactive conformation and preventing autophosphorylation. Molecular dynamics (MD) simulations also confirmed the structural stability of the EGFR-saccharopine complex, with RMSD values ranging between 0.13 and 0.23 Å, indicating minimal fluctuations and a stable binding pose. Binding free energy calculations using MM-PBSA analysis further showed a high binding affinity (−87.74 kcal/mol), with electrostatic interactions contributing significantly (−133.567 kcal/mol), confirming a strong inhibitory interaction with EGFR.

Table 1 In Silico Assay of Plants

The bioactive compounds from Abrus precatorius target the epidermal growth factor receptor (EGFR) pathway by directly binding to the receptor’s kinase domain, thereby preventing its activation and subsequent signaling. Stigmasterol, in particular, exhibits the strongest binding affinity to EGFR (−9.9 kcal/mol) (Table 1). This suggests that stigmasterol can effectively compete with ATP, blocking EGFR’s phosphorylation and disrupting its downstream signaling. The A. precatorius compounds interfere with this process by occupying the ATP-binding pocket, inhibiting the phosphorylation of tyrosine residues required for signal transduction.³⁶

Based on in vitro assay, saccharopine in Terminalia chebula leads to suppression of breast cancer cell proliferation and induction of apoptosis (see Figure 2). Western blot analysis confirmed that saccharopine treatment significantly reduced EGFR phosphorylation, preventing its activation and blocking downstream signaling pathways. Additionally, MTT cytotoxicity assays revealed that saccharopine dose-dependently reduced MCF-7 breast cancer cell viability, with a value of 103.2 μg/mL, indicating strong antiproliferative effects. Flow cytometry-based cell cycle analysis showed that saccharopine-induced G2/M phase arrest, preventing uncontrolled cancer cell division. Moreover, Annexin V/PI staining and caspase activation assays demonstrated that saccharopine significantly increased apoptosis, as confirmed by upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2, indicating its ability to induce programmed cell death via EGFR inhibition.

Figure 2 Breast Cancer Signaling Pathway Mechanism and Compound or Extract Intervention in Cell Regulation.

Extracts derived from Strobilanthes crispus that contains lutein, campesterol, stigmasterol, β-sitosterol, pheophytin a, 132 -hydroxy-pheophytin a, and 131 -hydroxy-132 -oxo-pheophytin also demonstrate encouraging outcomes in the treatment of breast cancer. The bioactive subfraction F3 effectively suppresses the movement and infiltration of MDA-MB-231 cells by reducing the expression of metastasis-associated markers like MMP-9, VEGF, and MUC1. This suppression is similar to the effects of established anticancer drugs such as curcumin and metformin, indicating its promise in stopping the spread of cancer cells (metastasis).^37,38

Based on in silico assay, Terminalia chebula has shown promise in blocking the EGFR by directly binding to its active site, stabilizing it in an inactive state, and preventing downstream oncogenic signaling (Table 1). Saccharopine, a bioactive compound from Terminalia chebula, directly binds to EGFR (PDB ID: 3W2S) with a high binding affinity of −9.7 kcal/mol, which is stronger than the standard reference ligand 17β-estradiol (−4.4 kcal/mol). Molecular docking simulations showed that saccharopine interacts with key EGFR active site residues, including GLN-791, MET-793, CYS-797, THR-854, and ASP-855, stabilizing the receptor in an inactive conformation and preventing autophosphorylation. Molecular dynamics (MD) simulations also confirmed the structural stability of the EGFR-saccharopine complex, with RMSD values ranging between 0.13 and 0.23 Å, indicating minimal fluctuations and a stable binding pose. Binding free energy calculations using MM-PBSA analysis further showed a high binding affinity (−87.74 kcal/mol), with electrostatic interactions contributing significantly (−133.567 kcal/mol), confirming a strong inhibitory interaction with EGFR.

The bioactive compounds from Abrus precatorius target the epidermal growth factor receptor (EGFR) pathway by directly binding to the receptor’s kinase domain, thereby preventing its activation and subsequent signaling. Stigmasterol, in particular, exhibits the strongest binding affinity to EGFR (−9.9 kcal/mol) (Table 1). This suggests that stigmasterol can effectively compete with ATP, blocking EGFR’s phosphorylation and disrupting its downstream signaling. The A. precatorius compounds interfere with this process by occupying the ATP-binding pocket, inhibiting the phosphorylation of tyrosine residues required for signal transduction.³⁶

Based on in vitro assay, saccharopine in Terminalia chebula leads to suppression of breast cancer cell proliferation and induction of apoptosis (see Figure 2). Western blot analysis confirmed that saccharopine treatment significantly reduced EGFR phosphorylation, preventing its activation and blocking downstream signaling pathways. Additionally, MTT cytotoxicity assays revealed that saccharopine dose-dependently reduced MCF-7 breast cancer cell viability, with a value of 103.2 μg/mL, indicating strong antiproliferative effects. Flow cytometry-based cell cycle analysis showed that saccharopine-induced G2/M phase arrest, preventing uncontrolled cancer cell division. Moreover, Annexin V/PI staining and caspase activation assays demonstrated that saccharopine significantly increased apoptosis, as confirmed by upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2, indicating its ability to induce programmed cell death via EGFR inhibition.

Extracts derived from Strobilanthes crispus that contains lutein, campesterol, stigmasterol, β-sitosterol, pheophytin a, 132 -hydroxy-pheophytin a, and 131 -hydroxy-132 -oxo-pheophytin also demonstrate encouraging outcomes in the treatment of breast cancer. The bioactive subfraction F3 effectively suppresses the movement and infiltration of MDA-MB-231 cells by reducing the expression of metastasis-associated markers like MMP-9, VEGF, and MUC1. This suppression is similar to the effects of established anticancer drugs such as curcumin and metformin, indicating its promise in stopping the spread of cancer cells (metastasis).^37,38

PI3K/AKT/mTOR Pathway

The PI3K/Akt/mTOR pathway is a critical intracellular signaling cascade that responds to nutrients, hormones, and growth factors, playing a significant role in tumor growth and proliferation. Central to this pathway is the PI3K heterodimer, consisting of a regulatory subunit (p85) and a catalytic subunit (p110), which is activated by receptor tyrosine kinases (RTKs).^39,40 Activated Akt, through phosphorylation by PDK1 and mTORC2, phosphorylates downstream targets, enhancing cell survival and growth, such as blocking pro-apoptotic factors (Bad, caspase-9) and activating mTORC1, which promotes protein synthesis and cell growth through S6 kinase and 4E-BP1 phosphorylation.⁴¹ Disruptions in the PI3K/Akt/mTOR pathway are common in cancer, often due to PI3K mutations, loss of the tumor suppressor PTEN, or overactivation of growth factor receptors, leading to increased PI3K activity and Akt activation. Activation in uncontrolled cell growth, tumor progression, metastasis, and treatment resistance.⁴²

Phaleria macrocarpa has the ability to inhibit the PI3K/Akt/mTOR pathway utilizing its bioactive components, which were identified using Liquid Chromatography–High-Resolution Mass Spectrometry (LC-HRMS). Computational investigations (Table 1) demonstrated that twelve out of fourteen compounds exhibit anticancer characteristics, namely affecting the PI3K/Akt signaling pathways. Apigenin strongly inhibits PI3K (−7.2 kcal/mol) and Akt (−7.2 kcal/mol), showed hydrogen bonding between apigenin and key residues in PI3K, preventing its activation, making it a potent candidate for targeting this pathway.⁴³

A study examined the impacts of Gallic acid (GA), a compound from Terminalia chebula, a polyphenol molecule that is recognized for its anti-tumor activities discovered to inhibit the advancement of triple-negative breast cancer (TNBC) HCC1806 cells via regulating the PI3K/AKT/EGFR and MAPK signaling pathways (Table 1). Gallic acid has a strong binding affinity with PI3K (PDB ID: 3APC), with a binding energy of −7.32 kcal/mol, indicating a stable interaction. GA formed hydrogen bonds with key residues GLN-1071 and GLU-981 which are crucial for PI3K activity. The formation of these bonds suggests that GA may interfere with PI3K phosphorylation, thereby preventing downstream activation of Akt. GA also exhibited a binding affinity toward Akt (PDB ID: 1GZK), with a binding energy of −5.61 kcal/mol. The docking analysis revealed that GA interacted with the TYR-417 residue of Akt through hydrogen bonding (1.9 Å). This interaction may lead to the suppression of Akt phosphorylation, thereby inhibiting its pro-survival signaling in cancer cells.⁴⁴

Ent-abietane diterpenoids such as Jolkinolide A and B, extracted from Euphorbia fischeriana, have strong anti-breast cancer properties. These compounds inhibit AKT phosphorylation, a key step in the PI3K/AKT/mTOR pathway (see Figure 2). By blocking this pathway, they reduce cancer cell proliferation and induce apoptosis.⁴⁵ The study also showed that GA from Terminalia chebula effectively inhibits the PI3K/Akt pathway in TNBC HCC1806 cells by reducing cell viability through cytotoxic effects, inducing apoptosis via caspase activation and mitochondrial dysfunction. Suppressing PI3K, Akt, and mTOR phosphorylation, leading to pathway inhibition and downregulating EGFR, preventing further activation of PI3K/Akt signaling⁴⁴ β-sitosterol (Table 2) inhibits glucose uptake in cancer cells by reducing GLUT1 localization on the membrane and suppressing hexokinase activity, leading to impaired glycolysis. Additionally, β-sitosterol downregulated key oncogenic proteins, including AKT, pAKT, mTOR, and HIF1α, while inhibiting PKC activity, thereby disrupting tumor cell metabolism and survival. Moreover, β-sitosterol increased TXNIP expression and reduced fibronectin levels, which contributed to decreased cancer cell migration and invasion, highlighting its potential as an anticancer agent.⁴⁶

Table 2 In vitro Assay on Plants

Isorhamnetin (Table 3) found in Antenoron filiforme significantly reduced tumor volume and weight, with the DOX + IS combination group exhibiting the most significant tumor suppression compared to the control and DOX-only groups. Immunohistochemistry (IHC) analysis confirmed that mTOR phosphorylation (p-mTOR) was markedly reduced in tumor tissues from the Isorhamnetin-treated group, correlating with decreased expression of p70S6K and 4E-BP1, key downstream effectors of mTOR signaling. Additionally, γ-H2AX expression was elevated, indicating increased DNA damage and apoptosis, which further contributed to tumor regression.⁴⁷ Strobilanthes crispus, a medicinal plant from Malaysia, exhibits anticancer properties its potent fraction, F3, derived from the leaves was analyzed in high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) and six bioactive components in F3, namely lutein, β-sitosterol, and stigmasterol (Table 3). The chemicals suppressed glycolysis and the PI3K/Akt pathway, resulting in decreased expression of AKT, pAKT, mTOR, and HIF1α. Additionally, it reduced the migratory ability of MDA-MB-231 cells, indicating their anti-glycolytic and anti-metastatic properties.^37,38

Taraxacum mongolicum extract exhibited significant anticancer properties when tested against triple-negative breast cancer (TNBC) cells. Dandelion extract disrupts the metabolic processes of glycerophospholipids and unsaturated fatty acids. Luteolin can inhibit the PI3K/AKT signaling pathway by reducing CHKA expression. This suppression leads to decreased phosphorylation levels of AKT, which is crucial for tumor cell proliferation and survival (see Figure 2). Studies conducted in living organisms demonstrated a decrease in tumor size and mass directly proportional to the dosage administered, with no impact on overall body weight.⁴⁸

Table 3 In vivo Assay on Plants

NF-Кb Pathway

The NF-κB pathway is crucial for breast cancer progression, modulating inflammation, immunity, cell proliferation, and survival. NF-κB is a protein complex composed of Rel family proteins (p65/RelA, RelB, c-Rel, p50, and p52) that control the transcription of several genes involved in the immune response and cell survival. In the setting of breast cancer, the NF-κB pathway is frequently and continuously active, which leads to the development of tumors and the survival of cancer cells. This activation occurs through the control of genes that produce proteins that prevent cell death (anti-apoptotic proteins), as well as substances that regulate inflammation (cytokines and chemokines) and the cell division process (cell cycle regulators).^49–51 The main function of this route is to primarily participate in the development of lymphoid organs and adaptive immune responses. However, it also plays a role in the advancement of breast cancer by controlling the activity of genes involved in cell movement and the spread of cancer cells to other parts of the body.⁵²

Russelioside A, a pregnane glycoside derived from the plant Caralluma tuberculata. The researchers extracted Russelioside A and examined its impact on NF-κB activity (see Figure 2) using the 4T1-NFκB-luciferase reporter cell line. It was found that Russelioside A effectively inhibited NF-κB transcriptional activity and the phosphorylation of p65, which is a crucial subunit of NF-Κb.⁵³

The second investigation conducted by Kamble et al, methanol extract derived from Chloroxylon swietenia (Table 2). The mechanism of action of its extract was associated with the induction of apoptosis via DNA fragmentation, actin cytoskeleton disorganization, and cell cycle arrest at the G2/M phase. Another notable study was around hyperoside a glycoside of the flavonoid class that is found in Zanthoxylum bungeanum. The study demonstrated that Hyperoside demonstrated its potential as a powerful inhibitor of the NF-κB pathway (see Figure 2) by causing mitochondrial malfunction and triggering apoptosis, triggering programmed cell death, and suppressing cell division in MCF-7 and 4T1 breast cancer cells.⁵⁴

α-Pinene in Tussilago farfara L. inhibits tumor invasion in highly metastatic MDA-MB-231 breast cancer cells by targeting the NF-κB signaling pathway (see Figure 2) and suppressing MMP-9 expression. 3D spheroid invasion assays confirmed that 50 μM. α-Pinene significantly reduced TNF-α-induced cancer cell invasion, while RT-PCR and MMP-9 promoter assays showed that α-Pinene dose-dependently downregulated MMP-9 transcription, preventing extracellular matrix degradation. Furthermore, Western blot and luciferase assays revealed that α-Pinene inhibited IKK phosphorylation, suppressed IκB degradation, and reduced p65/RelA activation, thereby blocking NF-κB-dependent transcription of pro-metastatic genes.⁵⁵ α-Phellandrene also in Tussilago farfara L. inhibits the NF-κB signaling pathway (see Figure 2) in MCF-7 breast cancer cells by suppressing TNF-α-induced NF-κB activation through inhibition of IκB degradation and reduced IKK phosphorylation, preventing NF-κB nuclear translocation.⁵⁶ Additionally, α-Phellandrene-induced G2/M cell cycle arrest and promoted apoptosis in a dose-dependent manner. Rutin in Tussilago farfara L. also suppresses DMBA-induced breast carcinogenesis by inhibiting the IL-6/NF-κB signaling pathway, which plays a key role in inflammation, tumor progression, and cancer cell survival significantly reduced IL-6, IL-1β, and TNF-α levels, thereby preventing NF-κB activation and downregulating oncogenic proteins Src1 and HSP90, which contribute to cancer cell survival and chemoresistance.⁵⁷

Eugenol, which demonstrated that this substance regulates the NOD1-NF-κB signaling pathway (see Figure 2) in triple-negative breast cancer cells. Eugenol inhibits the NF-κB signaling pathway in triple-negative breast cancer (TNBC) cells by suppressing NOD1 expression, an upstream activator of NF-κB, thereby reducing phosphorylated IκBα (p-IκBα) and NF-κB p65 levels, preventing its nuclear translocation. CCK8 and colony formation assays confirmed that eugenol dose-dependently inhibited TNBC cell proliferation, with IC₅₀ values of 16.84 μM in MDA-MB-231 and 27.25 μM in MDA-MB-453 cells, while transwell and wound healing assays revealed that eugenol reduced cell migration and invasion rates by up to 75.38%. Furthermore, DARTS-LC-MS/MS analysis confirmed that eugenol directly binds to NF-κB, stabilizing it in an inactive state.⁵⁸

Another study focused on chlorogenic acid, which is obtained from Euphorbia fischeriana (Table 1). This study showed that chlorogenic acid can trigger apoptosis and hinder breast cancer cell metastasis by inhibiting NF-κB activation in breast cancer cells by blocking IκBα phosphorylation, preventing NF-κB nuclear translocation, and reducing NF-κB target gene expression. Western blot analysis confirmed that CGA significantly downregulated NF-κB p65 expression and prevented IκBα degradation, leading to reduced transcription of MMP-9, COX-2, and VEGF, which are involved in metastasis and inflammation. Additionally, MTT and Annexin V/PI assays revealed that CGA selectively reduced breast cancer cell viability, increased apoptosis (via Bax and cleaved caspase-3 upregulation), and suppressed anti-apoptotic Bcl-2 expression.⁵⁹

An in vivo study of chlorogenic acid conducted by Zeng et al (Table 3) ⁵⁹ demonstrated that chlorogenic acid (CGA) inhibits NF-κB-mediated tumor progression in a BALB/c mouse model injected with 4T1 breast cancer cells, where CGA was administered intraperitoneally at doses of 20 mg/kg and 40 mg/kg every two days. Western blot analysis of tumor tissues confirmed that CGA downregulated NF-κB p65 and phosphorylated IκBα (p-IκBα), leading to reduced expression of metastatic markers such as MMP-9 and VEGF, which are critical for cancer cell invasion and angiogenesis. Additionally, flow cytometry analysis showed that CGA treatment increased CD4+ and CD8+ T-cell populations in the spleen, enhancing antitumor immunity, suggesting that CGA suppresses NF-κB activation while boosting immune-mediated tumor suppression in breast cancer.

JAK STAT3

The Janus kinase-signal transducer and activator of transcription 3 (JAK–STAT3) pathway is a pivotal signaling cascade that conveys information from extracellular chemical signals to the cell nucleus, culminating in the transcription of specific genes and subsequent cellular responses 43. The pathway is initiated when cytokines or growth factors bind to their corresponding receptors, causing the activation of receptor-associated Janus kinases (JAKs). Activated JAKs then phosphorylate specific tyrosine residues on the receptor, creating docking sites for STAT3 44. Upon binding, STAT3 is phosphorylated by JAKs, leading to its dimerization. The phosphorylated STAT3 dimers translocate into the nucleus, where they bind to particular DNA sequences, regulating the transcription of target genes involved in critical cellular processes such as proliferation, differentiation, apoptosis, and immune responses^60–62 In cancer, the JAK/STAT3 pathway is frequently overactive due to mutations, the absence of negative regulators such as SOCS3, or an increase in cytokine production. This leads to unregulated cell proliferation and the spread of cancer cells to other parts of the body.

7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone(ECN), which is a sesquiterpenoid derived from Tussilago farfara L. (Table 3) The cytotoxic effects of ECN effectively suppressed cell viability in a way that depended on the dosage. Western blot analysis revealed that ECN suppressed STAT3 phosphorylation at tyrosine 705, hence inhibiting dimerization and nuclear translocation. ECN inhibited STAT3 phosphorylation (p-STAT3) and downregulated JAK1, JAK2, and Src expression, leading to the suppression of the JAK-STAT3 signaling pathway. The inhibition resulted in reduced activation of STAT3 target genes, such as Bcl-2, Cyclin D1, and COX-2, and triggered programmed cell death through both external and internal routes ECN effectively suppressed tumor growth in a BALB/c nude mouse xenograft model injected with MDA-MB-231 breast cancer cells, where ECN was administered intraperitoneally at 1 mg/kg every two days for 21 days.⁵⁷

RAF/MEK/ERK Pathway

Proliferation, differentiation, survival, and apoptosis are regulated by the mitogen-activated protein kinase (MAPK) pathway, also known as the RAF/MEK/ERK signaling system. Extracellular growth factors or mitogens bind to receptor tyrosine kinases (RTKs), triggering the activation of RAS, a small GTPase. RAS, once activated, recruits and activates RAF kinases, including ARAF, BRAF, and CRAF. RAF kinases subsequently phosphorylate and stimulate the activity of MEK1 and MEK2, which are dual-specificity kinases. These kinases, in turn, phosphorylate and activate ERK1 and ERK2.^63,64

Sulforaphane, a naturally occurring chemical extracted from Brassica oleracea var. italica, as a powerful inhibitor of this specific pathway (Table 1).⁶⁵ The in silico study revealed that sulforaphane (SFN) directly interacts with RAF kinases (ARAF, BRAF, and CRAF), preventing their activation and downstream signaling in the RAF/MEK/ERK pathway. Molecular docking simulations demonstrated that SFN binds ARAF at Thr34 and Lys36, BRAF at Ser536, and CRAF at Lys399, Tyr340, and Tyr341, forming hydrogen bonds that stabilize these kinases in an inactive conformation. This binding disrupts the catalytic activity of RAF kinases, inhibiting MEK and ERK phosphorylation, thereby blocking proliferation and migration signals in breast cancer cells. Molecular dynamics simulations also confirmed that SFN binding alters the conformational flexibility of RAF kinases, further preventing MEK and ERK activation. Proteomic and phosphoproteomic analysis revealed that SFN affects the actin cytoskeleton by reducing the expression of focal adhesion and migration-related proteins, including paxillin, focal adhesion kinase (FAK), IQGAP1, ROCK, and PAK2, which play essential roles in cytoskeletal remodeling and tumor cell motility.

The in vitro study demonstrated that sulforaphane (SFN) inhibits the RAF/MEK/ERK signaling pathway (see Figure 2 and Table 2), leading to reduced proliferation and migration in triple-negative breast cancer (TNBC) cells. Western blot analysis confirmed that SFN significantly decreased RAF activation, which subsequently led to reduced MEK and ERK phosphorylation, preventing downstream signaling required for tumor progression. The inhibition of RAF/ERK signaling resulted in the suppression of oncogenic gene transcription, including MYC and Cyclin D1, thereby impairing cancer cell division and survival.

BCL-2 Pathway

The BCL-2 pathway is a major factor in cell survival and oncogenesis, particularly in breast cancer. This pathway involves a family of proteins, including Bcl-2, Bcl-X L, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B, which interact with BH3-domain pro-apoptotic proteins, hence controlling the balance between cell survival and death.⁶⁶ In breast cancer, the overexpression of Bcl-2 has been associated with treatment resistance and poor^67,68 The mechanism of the BCL-2 pathway in breast cancer relies on enhancing cell survival by blocking apoptosis. Overexpression of anti-apoptotic Bcl-2 proteins, such as Mcl-1, can result in apoptotic escape and treatment resistance in breast cancer.⁶⁹ Targeting BCL-2 has shown potential in enhancing vulnerability to therapy in estrogen receptor-positive breast cancer.⁷⁰ Moreover, the BCL-2 pathway can be efficiently targeted in combination with ionizing radiation to increase apoptotic cell death in breast cancer cells.⁷¹

The in silico study demonstrated that three lead phytochemicals from Ruellia tuberosa methanolic extract (RTME) directly interact with Bcl-2, potentially inhibiting its anti-apoptotic function and promoting apoptosis in breast cancer cells. Molecular docking analysis using Bcl-2 (PDB ID: 1G5M) revealed that 5-Hydroxymethylfurfural (−4.3 kcal/mol), n-Hexadecanoic acid (−4.4 kcal/mol), and Linoelaidic acid (−5.2 kcal/mol) exhibited strong binding affinities, stabilizing Bcl-2 in an inactive conformation. Further ligand–receptor interaction analysis showed that these compounds formed hydrogen bonds and hydrophobic interactions with key Bcl-2 residues (Table 1).

In vitro assay of the methanolic extract of Ruellia tuberosa extract also explains how the extract suppresses the Bcl-2 pathway in triple-negative breast cancer (TNBC) cells, leading to apoptosis (Table 2). The in vitro study demonstrated that the methanolic extract of Ruellia tuberosa (RTME) suppresses the Bcl-2 pathway in TNBC cells, leading to apoptosis (see Figure 2). Western blot and qRT-PCR analysis confirmed significant Bcl-2 downregulation, while JC-1 staining revealed mitochondrial destabilization and cytochrome c release, triggering apoptosis. Additionally, RTME increased the Bax/Bcl-2 ratio, activated caspase-9 and caspase-3, confirming intrinsic apoptosis. These findings suggest that RTME induces apoptosis in TNBC cells by inhibiting Bcl-2, promoting mitochondrial dysfunction, and activating caspase signaling.

Toosendanin (TSN) from MeLia toosendan Sieb.et Zucc activates caspase-3 via the mitochondrial apoptotic pathway by the following mechanisms: First, TSN decreases the expression of anti-apoptotic Bcl-xL and increases pro-apoptotic Bax, thereby triggering changes in mitochondrial membrane permeability and the release of cytochrome c to the cytosol. Cytochrome c then binds to Apaf-1 to form apoptosomes, which recruit and activate pro-caspase-9. Active caspase-9 further cleaves pro-caspase-3 into active caspase-3, which executes cell death by breaking down substrates such as PARP, causing chromatin condensation and DNA fragmentation. This activation of caspase-3 is measurable as an increase in the number of Annexin V⁺ cells and an increase in the level of activated caspase-3 in MDA-MB-231 cells.

Isotoosendanin (ITSN) in MeLia toosendan Sieb.et Zucc induced apoptosis through the mitochondrial-cas¬pase pathway, but with less intensity than Toosendanin. Mechanistically, ITSN decreased the expression of Bcl-xL and slightly increased Bax, thus causing mitochondrial membrane permeability and the release of cytochrome c. Cytochrome c combines with Apaf-1 to form apoptosomes that activate pro-caspase-9, and active caspase-9 then cleaves pro-caspase-3 into active caspase-3. Activation of caspase-3 by ITSN was detected as an increase in the number of Annexin V⁺ cells and an increase in the level of activated caspase-3, but at a much more moderate level, corresponding to the IC₅₀ value of ITSN (~7.42 µM).

The in vivo study (Table 3) also demonstrated that RTME suppresses the Bcl-2 pathway, induces apoptosis, and reduces tumor growth in a Balb/C mouse model without causing significant toxicity. Blood biochemical analysis confirmed that liver, kidney, and lung function markers remained within normal ranges, while histopathological examination of major organs showed no structural damage, indicating that RTME is safe at therapeutic doses. Furthermore, mice treated with RTME exhibited a significant reduction in tumor volume and weight.

p53 Pathway

The p53 pathway is a significant pathway for suppressing tumors by controlling DNA repair, cell cycle progression, cell death, and senescence which hinders the spread of aberrant cells. p53 is a transcription factor that is present in both the nucleus and cytoplasm.⁷² It has the ability to bind DNA in a specific manner and control the activity of certain genes. Cellular levels of the p53 protein are kept relatively low due to stringent regulation by its negative regulators MDM2 and MDMX.⁷³ These regulators encourage the breakdown of p53 through a process called ubiquitination. In response to DNA damage, p53 induces the expression of p21, a cyclin-dependent kinase inhibitor blocking CDK2 and CDK1, leading to a cell cycle arrest at the G1/S and G2/M checkpoint, allowing time for DNA repair or enabling cellular senescence and preventing the proliferation of damaged cells.⁷⁴ When p53 induces senescence, this elevates the p21 and PAI1 genes, leading cells to permanently stop proliferating in response to irreparable DNA damage or other stressors.⁷⁵ Senescence acts as a tumor suppressor process by inhibiting the growth of damaged cells.⁷⁶ P53 exhibits control over cellular metabolism by suppressing glycolysis and enhancing oxidative phosphorylation via the transcriptional activation of genes.⁷⁷ P53 can stimulate the expression of autophagy-related genes (Atgs) and suppress mTOR, a vital controller of autophagy. Autophagy promotes cell survival during periods of limited nutrients, while excessive autophagy results in cell death.⁷⁸

The in vitro study (Table 2) shows moringin, an isothiocyanate from Moringa oleifera, activates the p53 pathway (See Figure 2) in MCF-7 and MDA-MB-231 breast cancer cells with IC50 value of 20.75 µM and: 23.04 µM after 72 hours, leading to apoptosis and cell cycle arrest. Western blot analysis confirmed that moringin significantly increased p53 expression, which in turn activated its downstream pro-apoptotic targets, including Bax, NOXA, and PUMA, promoting programmed cell death. Additionally, p53 upregulation was associated with increased expression of p21, a key cyclin-dependent kinase (CDK) inhibitor, resulting in G1-phase cell cycle arrest and preventing uncontrolled cancer cell proliferation.

SKP/p21

The SKP/p21 signaling pathway plays a crucial role in controlling the progression of the cell cycle and programmed cell death (apoptosis), which are vital events in the development and progression of breast cancer.⁷⁹ The SCF complex, composed of the SKP1-CUL1-F-box protein, acts as an E3 ubiquitin ligase, promoting the ubiquitination and subsequent proteasomal destruction of certain target proteins.⁸⁰ This degradation is crucial for the regulation of the cell cycle. P21, also called Cip1/Waf1, is a protein that inhibits the activity of cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase 4 (CDK4) complexes.^81,82 Additionally, it acts as a tumor suppressor, preventing the formation and growth of tumors. The interaction between SKP2 and p21 holds great significance in the setting of breast cancer, especially in aggressive subtypes like triple-negative breast cancer (TNBC).⁸³ SKP2, an F-box protein found in the SCF complex, is commonly upregulated in breast cancer, resulting in increased ubiquitination and breakdown of p21.⁸⁴ The decrease in p21 levels reduces its ability to inhibit cyclin-CDK complexes, leading to uncontrolled cell proliferation and poor programmed cell death. This ultimately promotes tumor growth and advancement.⁸⁵

Recent studies have emphasized the considerable capacity of plant extracts to hinder the growth of breast cancer cells.⁸⁶ Eleutherine bulbosa (Mill). Urb (Table 2). The ethyl acetate extract inhibit transcription of TCF/β-catenin (Table 2).⁸⁷ The ethyl acetate extract (EAESO) shown high potency by effectively interrupting the cell cycle at the G0-G1 phase. The ethyl acetate increases the expression of p21 and p27 proteins and becomes a complex bond with Cyclin D and Cyclin Dependent Kinase 4/6 (CDK), which would inhibit the phosphorylation PRB (retinoblastoma protein). This suggests that EAESO has the potential to be used as a therapeutic agent for breast cancer by arresting the cell cycle and inducing apoptosis.

A study conducted on the ethyl acetate extract of Antenoron filiforme. showed promising results in blocking the SKP2/p21 pathway. The in silico analysis (Table 1) demonstrated that quercetin and its analogs in Antenoron filiforme could directly bind to Skp2, potentially inhibiting its function and stabilizing p21. Molecular docking simulations revealed strong interactions between quercetin and Skp2 (PDB ID: 2ASS), with key hydrogen bonds forming at Ser343, Ser391, Arg344, and Ser238, ensuring high binding affinity (Glide scores < −6 kcal/mol). Molecular dynamics (MD) simulations were conducted over 20 ns, confirming that the quercetin-Skp2 complex remained structurally stable, with an RMSD of ~4.76 Å and strong interactions within the 240–320 residue region of Skp2. The root-mean-square fluctuation (RMSF) analysis showed that quercetin maintained stable binding throughout the simulation. These results indicate that quercetin and its analogs may function as Skp2 inhibitors, preventing p21 degradation and thereby reinforcing G1/S cell cycle arrest in TNBC cell.

The in vitro assay (Table 2) shows that ethyl acetate extract induces G1/S cell cycle arrest in TNBC cells via the Skp2-p21 pathway (see Figure 2). AF-EAE upregulate p21 (CDKN1A) expression, leading to CDK6 and CCND1 downregulation, thereby inhibiting Rb phosphorylation and E2F-mediated S-phase entry. Concurrently, AF-EAE suppressed Skp2, preventing p21 ubiquitination and stabilizing its function as a CDK inhibitor.

The in vivo study (Table 3) demonstrated that Antenoron filiforme ethyl acetate extract effectively suppresses TNBC tumor growth in a xenograft mouse model. Tumor volume measurements revealed that the extract significantly inhibited tumor growth compared to the control group (p < 0.05). Histological analysis (H&E staining) confirmed extensive tumor cell membrane and nuclear disruption, suggesting apoptosis or reduced proliferation. Notably, body weight and major organ histology (heart, liver, spleen, lung, kidney) showed no significant toxicity, indicating AF-EAE’s safety profile.

Discussion

Several bioactive compounds from medicinal plants have shown significant anticancer properties by targeting key molecular pathways involved in cancer progression. Among pure phytoconstituents, 17-Hydroxy-jolkinolide B showed the greatest potency with an IC₅₀ of 1.1 µg/mL against MDA-MB-231 cells, while the Toosendanin achieved an IC₅₀ of 0.095 µM in the same line, and Kaempferol exhibited an IC₅₀ of 43 µM in MDA-MB-231 cells by triggering G₂/M arrest and caspase-mediated apoptosis. In parallel, the ethyl acetate fraction of Syzygium samarangense leaves demonstrated an IC₅₀ of 7.2 µg/mL in MCF-7 cells while sparing normal breast epithelial cells. The ethyl acetate extract of Eleutherine bulbosa bulbs attained an IC₅₀ of 147.1 µg/mL and induced G₀/G₁ arrest and apoptosis, and the dichloromethane fraction of Strobilanthes crispus leaves effectively inhibited PI3K/AKT/mTOR signaling to reduce cell migration and metastatic potential.

Limitations

Breast cancer remains one of the most challenging diseases to treat, with conventional therapies often coming with severe side effects and limited long-term success. This has fueled interest in plant-derived compounds as potential alternative or complementary treatments. Despite these encouraging findings, translating these compounds into viable treatments presents challenges. Many plant-based molecules struggle with bioavailability, metabolic stability, and consistency in effectiveness. Most of the studies compiled in this review used crude extracts or fractions as test materials, while data on pure compounds are still minimal. Only a few studies evaluated isolated molecules, so we cannot yet isolate the specific contribution of each component to antiproliferative activity. This limitation hinders understanding the molecular mechanism of action and the pharmacokinetic hurdles associated with the selected compounds. The absence of acute/sub-chronic toxicity (LD₅₀) and safe-dose (NOAEL) data hinders our ability to judge therapeutic windows and anticipate off-target effects.

Despite potent in vitro anticancer activity, translation of these agents is hampered by significant pharmacokinetic and safety barriers. 17-Hydroxy-jolkinolide B, though highly cytotoxic (IC₅₀ = 1.1 µg/mL), is essentially insoluble in water and exhibits very low oral bioavailability with rapid hepatic clearance, necessitating specialized nanoparticle formulations to achieve meaningful plasma levels and raising concerns about a narrow therapeutic window. Toosendanin demonstrates sub-micromolar efficacy (IC₅₀=0.095 µM) but is limited by well-documented neurotoxicity—blockade of synaptic transmission—and hepatotoxicity in rodent studies, compounded by poor aqueous solubility that complicates reliable dosing. Kaempferol, despite inducing G₂/M arrest and apoptosis at 43 µM, suffers from extensive first-pass glucuronidation and sulfation, yielding oral bioavailability below 2% and rapid renal elimination, which precludes achieving therapeutic concentrations without supraphysiological dosing. The flavonoid-rich ethyl acetate fraction of Syzygium samarangense (IC₅₀ = 7.2 µg/mL) remains an unstandardized botanical extract: its complex, variable composition and unknown ADME/Tox profile mean batch-to-batch inconsistencies and undefined safety margins hamper in vivo assay. Similarly, the Eleutherine bulbosa ethyl acetate fraction (IC₅₀= 147.1 µg/mL) has only modest potency and lacks any pharmacokinetic or systemic toxicity data, making its therapeutic index and metabolic stability wholly speculative. Finally, the Strobilanthes crispus dichloromethane fraction, though effective in suppressing PI3K/AKT/mTOR signaling in vitro, is a hydrophobic mixture with no solubility enhancement, absorption studies, or safety evaluations, leaving its in vivo feasibility untested and its translational readiness very low.

Future Research

In addition to biological effectiveness, drug formulation and delivery advancements will play a key role in the future of plant-derived cancer therapies.⁸⁸ Nanotechnology and other innovative drug delivery systems may help improve the absorption and targeted action of these natural compounds, overcoming their current limitations.

Many of these plant compounds suffer from poor solubility or stability, which can be mitigated by nanoformulation. For example, folate‐modified PLGA–PEG nanoparticles carrying apigenin achieved much more potent cytotoxicity against breast cancer cells: the IC₅₀ of folate–PLGA–PEG–apigenin was ~13.3 μM versus ~50.2 μM for free apigenin (ie, ~3.8× enhanced potency). Similarly, polymer–lipid hybrid nanoparticles (PLGA + lecithin) loaded with apigenin (100–175 nm size) showed rapid initial release followed by sustained delivery, improved antioxidant activity. They significantly increased the killing of MCF-7 and MDA-MB-231 cells compared.⁸⁹ Phytosterols have also been nano-engineered: stigmasterol was co-encapsulated with doxorubicin in hyaluronic acid-coated PEGylated liposomes targeting the CD44 receptor. The HA-PEG–Liposome–doxorubicin–stigmasterol (HA-DOX-STS-lipo) particles (~174 nm) released DOX in acidic tumor-mimicking conditions and selectively accumulated in CD44⁺ MDA-MB-231 tumors, greatly enhancing antitumor efficacy in vitro and in vivo.⁹⁰

Other targeted carriers include isorhamnetin: it was loaded into carboxymethyl chitosan nanoparticles with a polydopamine coating, forming Iso/CMC-PDA nanospheres. This formulation targeted tumor cells and inhibited cervical cancer growth in vitro⁹¹ (suggesting it might be adapted to breast or other tumors). Likewise, the diterpenoid 17-hydroxy-jolkinolide B (17-HJB) was formulated in hyaluronic-acid–coated liposomes (HA-Lip-HJB) of ~130 nm. The HA-targeted liposomes greatly increased uptake via CD44, inhibited breast cancer cell migration (via blocking EMT), and suppressed lung metastasis in 4T1 tumor-bearing mice.⁹² Polymeric nanoparticles have also improved delivery of flavonoids like kaempferol: for instance, PLGA NPs carrying kaempferol selectively killed ovarian (and by extension likely breast) cancer cells while sparing normal cells.⁹³ In that study, PLGA‐kaempferol NPs had potent cytotoxicity on tumor cells without harming normal cells, outperforming free kaempferol.⁹³

Several studies have explored combining these phytocompounds with standard drugs to achieve potentiatism or to overcome resistance. Toosendanin, a triterpenoid from Melia toosendan, blocked late-stage autophagy in triple-negative breast cancer (TNBC) cells. When Toosendanin was combined with the topoisomerase-I inhibitor irinotecan (or its metabolite SN-38) in MDA-MB-231 xenografts, it prevented chemotherapy-induced protective autophagy and significantly increased apoptosis and tumor shrinkage compared to irinotecan alone.⁹⁴ Likewise, apigenin has been shown to modulate anthracycline efficacy: co-treatment with apigenin altered doxorubicin-induced lipid metabolism and is predicted to interact at drug-efflux transporters (ABC proteins) via AKT/MYC pathways,⁹⁵ hinting that apigenin might sensitize specific breast cancer cells to doxorubicin. Stigmasterol and doxorubicin were co-formulated in the same targeted liposome,^90,96 yielding synergistic killing of CD44⁺ cancer cells. Although not yet tested in breast cancer, other flavonoid–drug combinations (eg, kaempferol with sorafenib) have shown additive effects in model studies.

For complex extracts, standardization is crucial. Syzygium samarangense ethyl acetate extract has been thoroughly profiled: researchers used TLC, FTIR, LC-MS/MS, and total phenol/flavonoid assays to confirm a high flavonoid content.⁹⁷ The extract is shown to have potent antioxidant capacity (comparable to ascorbic acid) and cytotoxicity (IC₅₀ ≈ 7.2 μg/mL) against MCF-7 cells, inducing apoptosis (DNA fragmentation, caspase-3 activation) without harming normal breast epithelial cells. Such phytochemical fingerprinting ensures consistency and helps link active constituents to bioactivity. Similarly, Eleutherine bulbosa bulb extracts have been investigated: network‐pharmacology and in vitro assays showed E. bulbosa extract triggers ~93.6% apoptosis in T47D breast cancer cells and causes cell-cycle arrest⁹⁸ These efforts identify key pathway effects (p53, MAPK, PI3K/Akt) and support dose standardization. Although formal phytochemical standardization of Russelioside A (a purified pregnane glycoside) has not been reported, its anti-TNBC activity has been documented in cell and animal models. Fractionation studies identified a potent anticancer sub-fraction from the DCM extract. One sub-fraction, SC/D-F9, killed both ER⁺ (MCF-7) and TNBC (MDA-MB-231) cells at low concentrations while sparing normal MCF-10A breast cells SC/D-F9 was even more cytotoxic than tamoxifen or doxorubicin at comparable doses, and it induced caspase-3/7–mediated apoptosis.⁹⁹ Such fractionation and bioactivity-guided isolation effectively “standardize” the extract by defining an active component, which can then be further characterized (eg by LC-MS) and used in targeted delivery.

Various solubilization strategies have been used to improve oral uptake and circulation time. A recent study formulated apigenin as a self-nanoemulsifying drug delivery system (SNEDDS) using bioactive excipients (Gelucire 44/14, Tween 80, PEG 400). This SNEDDS dramatically increased apigenin’s C_max and AUC: relative oral bioavailability in rats was ~3.3–3.8× higher than crude apigenin.⁸⁹ Likewise, formulating apigenin into polymeric nanoparticles both solubilized the drug and provided controlled release, enhancing in vitro activity. Similar approaches (lipid NPs, cyclodextrins, micronization) could boost the bioavailability of other hydrophobic compounds here. For instance, kaempferol–like flavonols often undergo rapid Phase II metabolism; encapsulation in PEGylated carriers or use of prodrug linkers might extend their half-life (strategies successful for taxanes or resveratrol¹⁰⁰). Although not yet reported for Russelioside A or Toosendanin, glycosylated triterpenoids might benefit from pH-sensitive polymeric NPs or inclusion complexes to improve solubility and protect against premature degradation. By refining extraction methods, optimizing bioavailability, and conducting rigorous clinical trials, we can unlock the full potential of these natural compounds. Ultimately, the goal is not only to develop more effective treatments but also to provide safer, less toxic alternatives that improve both survival rates and quality of life for breast cancer patients.

Conclusions

This review underscores the therapeutic potential of plant-derived compounds in targeting key oncogenic pathways in breast cancer, including EGFR, PI3K/AKT/mTOR, NF-κB, and RAF/MEK/ERK. Several compounds such as saccharopine, apigenin, isorhamnetin, russelioside A, and sul demonstrate promising in vitro and in vivo activity through induction of apoptosis, inhibition of metastasis, and cell-cycle arrest. However, translation into clinical application remains limited due to poor bioavailability, metabolic instability, and lack of compound-specific pharmacokinetic data.

Most studies rely on crude extracts or semi-purified fractions, hindering the delineation of specific molecular mechanisms. To address these limitations, future research should focus on isolating active constituents, standardizing extract profiles, and applying advanced delivery systems such as nanoparticle-based formulations. These strategies may significantly improve pharmacological performance and safety, facilitating the development of plant-based therapeutics as effective alternatives or adjuncts in breast cancer management. While these compounds exhibit remarkable anticancer properties, further research is needed to enhance their bioavailability, stability, and clinical application. Developing advanced drug delivery systems, optimizing combination therapies, and conducting rigorous clinical trials will be essential to integrating these natural compounds into mainstream breast cancer treatment. By leveraging the power of plant-derived bioactives, future therapies may offer safer and more effective alternatives for patients worldwide.