Exploring the anti‐cancer potential of dietary phytochemicals for the patients with breast cancer: A comprehensive review

Abstract Background The most common and deadly cancer in female is breast cancer (BC) and new incidence and deaths related to this cancer are rising. Aims Several issues, that is, high cost, toxicity, allergic reactions, less efficacy, multidrug resistance, and the economic cost of conventional anti‐cancer therapies, has prompted scientists to discover innovative approaches and new chemo‐preventive agents. Materials Numerous studies are being conducted on plant‐based and dietary phytochemicals to discover new‐fangled and more advanced therapeutic approaches for BC management. Result We have identified that natural compounds modulated many molecular mechanisms and cellular phenomena, including apoptosis, cell cycle progression, cell proliferation, angiogenesis and metastasis, up‐regulation of tumor‐suppressive genes, and down‐regulation of oncogenes, modulation of hypoxia, mammosphere formation, onco‐inflammation, enzymatic regulation, and epigenetic modifications in BC. We found that a number of signaling networks and their components such as PI3K/Akt/mTOR, MMP‐2 and 9, Wnt/‐catenin, PARP, MAPK, NF‐κB, Caspase‐3/8/9, Bax, Bcl2, Smad4, Notch1, STAT3, Nrf2, and ROS signaling can be regulated in cancer cells by phytochemicals. They induce up‐regulation of tumor inhibitor microRNAs, which have been highlighted as a key player for ani‐BC treatments followed by phytochemical supplementation. Conclusion Therefore, this collection offers a sound foundation for further investigation into phytochemicals as a potential route for the development of anti‐cancer drugs in treating patients with BC.


| INTRODUCTION
Breast cancer (BC) is the most common and frequent malignancy among females, and it is the second most frequent carcinoma and a significant cause of cancer-associated death worldwide. This cancer is a multifactorial disease and various factors, including demographic, oxidative stress, bacterial infection, reproductive, hormonal, hereditary, and lifestyle contribute to its occurrence. 1 A number of conventional therapeutic options such as surgical resection, radiotherapy, chemo-radiotherapies (e.g., adjuvant chemotherapies and neoadjuvant therapy), hormonal therapies, monoclonal antibodies, immunotherapy, and small molecular inhibitors are available for the patients with BC. 2,3 However, these therapeutic modalities have drawbacks, bearing side effects and toxicities. Thus, new approaches and strategies are needed to manage patients with BC effectively to minimize the limitations, such as increasing resistance to conventional therapeutics, side effects, and toxicities of existing treatment modalities. Interestingly, alternative medicines (with fewer side effects) for patients with BC, especially metastatic cancer, have been developed.
Phytochemicals are an essential natural resource for anti-cancer medicine. They are safe, non-toxic, costeffective, and readily available sources from villages to cities and underdeveloped to developed countries. 4 Currently, medicinal plants or their derivatives account for about 70% of the anti-cancer compounds, thus, playing the lead role in developing anti-cancer drugs. 5,6 Initially, natural plant extracts have showed higher anti-tumor responses and better pharmacological or bioactivity with less toxicity in patients with advanced BC (Table 1). [37][38][39][40] For example, anti-cancer compounds from Curcuma longa, Piper longum, Nigella sativa, Murrayakoenigii, Amora rohituka, Withania somnifera, and Dimocarpus longan possess anti-cancer activity against various cancers, especially anti-BC properties. 8,25,36,[41][42][43][44] Latter specific phytochemicals have been identified as a new source of anti-cancer agents from plant extract to decrease the negative effects of cancer chemotherapies in recent research. [45][46][47][48] These natural agents can target several BC-related pathways and provide protective activity against breast malignancies, which play a significant role in preventing and managing patients with BC. 46,49 Several individual studies exhibited phytochemicals had anti-cancer property through several mechanisms. [50][51][52] However, a comprehensive summary on precise anti-cancer mechanisms including apoptosis induction, cell cycle, and cell proliferation regulation, inhibition of angiogenesis and metastasis, regulating hypoxia-inducible factor, suppressed mammosphere formation, onco-inflammation inhibition, controlling enzyme activity, signal transduction regulation, epigenetic and immune regulation have not been reported collectively. Therefore, in this review, we have discussed various phytochemicals with their major sources, structure, and their possible anti-cancer pathways in the BC, thereby providing an aggregative source of information on potential natural anti-cancer resources.

| PHYTOCHEMICALS TARGETING BC CELLS
Therapeutic strategies against BC include surgery chemoradiotherapies, adjuvant/neoadjuvant therapies, hormonal therapies, monoclonal antibodies, immunotherapy, nanomedicines, and small molecular inhibitors. 99 T A B L E 1 Summary of plants extract and their anti-cancer activity in human breast cancer cell line. chloroform

Kempferol
Green leafy vegetables such as broccoli, spinach, and kale, and herbs such as dill, chives, and tarragon, onion, leeks 60 Lutein Green leafy vegetables such as broccoli, spinach peas, lettuce, and egg yolks 58 Lycopene Tomato, watermelon, pink guava, papaya, pink grapefruit, and dried apricots passionflower fruit 62 Naringenin Fruits like citrus species and tomatoes 63 Nimbolide Leaves and flowers of neem (Azadirachta indica) 64 Pharbilignan C Pharbitidis semen, the seed of morning glory (Pharbitis nil) 88 Pterostilbene Blueberries, grapes, and tree wood 89 Punicalagin Pomegranate (Punica granatum) 69 Quercetin Nuts, apples, onions, olive oil green tea, broccoli, red grapes, dark cherries 90 Sanguinarine Rhizome of bloodroot (Sanguinaria canadensis) 65 Withaferin However, limitations such as resistance, compromised efficacy, and side effects of conventional therapies limit their clinical applications. Thus, plant-derived anti-cancer agents with less or no toxic effects can be an alternative chemotherapeutic option. Anti-cancer activity of phytochemicals is dependent on their multi-targeted mechanism of action. Since carcinogenesis is a multistep process involving multiple signaling mechanisms, numerous phytochemicals targeting the altered signaling in cancer are considered promising anti-cancer therapeutics. 100 Phytochemicals targeting signaling pathways in cancer are summarized ( Table 3). The following sections outline the role of potentially bioactive compounds against BC cells with their possible molecular mechanism.

| Inhibition of cell proliferation
Cellular proliferation is essential for all multicellular organisms to develop bodies and organs during embryogenesis. However, in the case of cancer, abnormal cell proliferation is due to changing the expression or activity of protein associated with cell proliferation or cell cycle regulation. Phytochemicals and their derivatives can inhibit the growth and expansion of BC cells by targeting cell cycle regulatory proteins. 172 For example, the naturally active compound formononetin (25 μΜ) suppresses tumor growth and angiogenesis in MCF-7 and MDA-MB-231 tumor models by targeting the FGFR2-mediated Akt signaling pathway. 101 Treatment of MCF-7 cells by silibinin (50-200 μmol) prevented cell proliferation through modulating the expression of apoptosis-related proteins such as Bcl-xl, bak, p53, p21, 107 whereas sesamin (100 μM) could inhibit MCF-7 cell proliferation by down-regulating cyclin D1 expression. 102 Curcumin mediated its anti-proliferative activity against BC (MDA-MB-231 and BT-483) cells by regulating the expression of NF-κB, cyclin D1, CDK4, and MMP1. 103 Chen et al. noted that Genistein (40-100 μM) exhibited anti-proliferative activity by deactivating the IGF-1R-PI3K/Akt signaling pathway along with increasing Bax/Bcl-2 expressions in MCF-7 cells, 104 whereas lycopene showed similar activities by increasing Bax expression without changing Bcl-xL in MDA-MB-468 cancer cells. 105 Scheckel KA reported that the anti-proliferative activity of rosmarinic acid (20 μmol/L) is associated with a decrease in COX-2 expression and activation of AP-1 and ERK1/2 in MCF-7 cells. 106 Harrison et al. reported that apigenin arrests the cell cycle at the G2/M phase, followed by down-regulation p-Akt in MDA-MB-468 cancer cells. 108 Furthermore, enterolactone (ENL) has been shown to suppress cell proliferation by lowering uPA-mediated plasmin activation and down-regulation of MMP-2 and MMP-9 in MDA-MB-231 cells. 109 Therefore, phytochemicals could act as potent inhibitors of cell proliferation in BC cells by suppressing cell survival signaling, cell cycle regulatory protein, and regulating apoptosis-related proteins.

Structure Source
Ref.

| Apoptosis inductions
Apoptosis, a programmed cell death mechanism, plays a crucial role in cancer pathogenesis and maintenance by regulating cell death and survival based on specific signals. 173 Apoptosis can be executed via two mechanisms, that is, the extrinsic and intrinsic mitochondrial pathways. 174 Both of these pathways are regulated through several regulatory proteins. 175 The extrinsic pathway, for instance, is associated with the Fas ligand, Fas-associated protein with death domain initiator pro-caspase-8, and many caspases contributing to the cascade amplification. 176 In contrast, the intrinsic pathway involves apoptosis-related proteins such as Bax, Bak, Bcl2, Cyto-c, adaptor protein Apaf-1, and active caspases. 177 Thus, regulating these proteins by phytochemicals could be an alternative for better management of patients with BC. Ginsenoside Rh1 ( 119 Also, lycopene and EGCG induced apoptosis by up-regulating the expression of p53 and Bax/Bcl-2 ratio with downregulating telomerase and P13K/AKT in MCF-7 and T47D cancer cells. 83,113 Furthermore, curcumin and resveratrol can induce apoptosis through the regulation of Bax/Bcl2, whereas thymoquinone, apigenin, pterostilbene, and sulforaphane are associated with apoptosis by regulating caspases cascade and signal transduction mechanism in multiple human BC cells. 144,164,[178][179][180][181] Therefore, phytochemicals inhibit BC progression by apoptosis induction, which mediates either intrinsic or extrinsic, and sometimes both pathways.

| Inducing cell cycle arrest
The cell cycle is a principal physiological mechanism regulating tissue homeostasis and development in multicellular organisms. Therefore, alterations in the cell cycle cause cancer. Thus, novel strategies have been developed targeting altered cell cycles or components. Checkpoints in the cell cycle arrest cell cycle progression in the case of DNA damage, allowing time for DNA repair. 182,183 In numerous breast carcinomas, phytochemicals inhibit the passage of the cell cycle by modulating checkpoints components such as lowering cyclins (D1 and E) levels and cyclin-dependent CDKs etc., and by up-regulating the expression of proteins such as CDK inhibitors (p21 and p27). For example, quercetin halts the cell cycle at the G2/M phase by raising Cdk-inhibitor, especially p21CIP1/WAF1 and its associated protein Cdc2-cyclin B1 complex in MCF-7 cancer cells. 120 Treatment of coumestrol (50 μM) caused cell cycle arrest at the G1/S phase, followed by upregulations of regulatory protein CDKI and p21 and p53 in MCF-7 cells. 122 Also, taiwanin A treatment was associated with the up-regulation of p21, p27, p53, and p-p53 in MCF-7 cells in a dose-dependent manner. 121 Kim et al. reported that ginsenosides (100 μM) had arrested the cell cycle at G0/G1 phase via inhibiting Cyclin D1, Cyclin E2, and their associated enzyme CDK4, along with upregulating p15INK4B, p21WAF1/CIP1 and p55 level in MCF-7 cells. 123 Another phytochemical, kaempferol, reduced MCF-7 cell growth by down-regulating cathepsin D, cyclin E, and cyclin D1 expressions and up-regulating Bax and p21. 124 Furthermore, thymoquinone (100-200 μM) significantly inhibited the expression of cyclin D1 and E, resulting in promoting the survival of multiple BC (MCF-7, T47D, and MDA-MB-231) cells. 125 Moreover, naringenin is an essential plant chemical that can regulate cell cycle checkpoints by suppressing CDK4, CDK6, and CDK7 with up-regulating p18, p19, and p21 in BC (HTB26 and HTB132) cells. 126 Altogether, phytochemicals halt the progression of the cell cycle of BC cells by either inhibiting the expression and activity of cyclins (B1, D1, and E) and CDKs (4,6,7) or increasing the expression of CDKs inhibitors (p18, p21, p27, and p53).

| Inhibition of hypoxia-inducible factor
Tumor hypoxia refers to cells being deprived of normal oxygen due to low oxygen levels in the tumor microenvironment. Hypoxia induces multiple signaling cascades such as MAPK, phosphatidyl-inositol 3-kinase (PI3K), HIF, and NF-κB pathways in cancer cells, leading to feedback loops of both positive and negative, and enhancing or diminishing hypoxic effects. 187 It was also found that hypoxia regulates several cellular phenomena, such as the expression of drug efflux proteins, apoptosis, DNA damage, the efficiency of chemotherapy, angiogenesis, and metastasis. 187 Therefore, targeting hypoxia-inducible factor 1 (HIF-1), a crucial component of hypoxia, could be a potential strategy against hypoxia-induced cancer cell growth and progression. Several phytochemicals can directly inhibit HIF-1-related genes, including GLUT-1, CDKN1A, and VEGF. This inhibition ultimately results in a decrease in tumor angiogenesis, migration, and chemotaxis. According to Wang et al. isoliquiritigenin (25-50 μM) treatment suppressed P13K/Akt, NF-κB signaling pathways via modulating the expression of VEGF, HIF-1α, and MMP-2, MMP-9 expressions, leading to limit the migration of MDA-MB-231 cells. 137 Riby et al. demonstrated that 3,3-diindolylmethane (50 μM) exhibited anti-cancer activity by decreasing the expression of hypoxia-responsive factors such as furin, and glucose transporter-1, VEGF, enolase-1, and phosphofructokinase in hypoxic specific MDA-MB-231 cells. 141 In addition, lyciumbarbarum polysaccharides inhibit HIF-1α protein aggregation by altering mRNA levels and VEGF mRNA expression leading to inhibit the nuclear translocation of HIF-1α in MCF-7 cells. 142 Another study showed that EGCG (50 μg/mL) inhibits breast tumor formation, proliferation, migration, and angiogenesis by inhibiting HIF-1α in MCF-7 and MDA-MB-231 cells. 140 Wang et al. noted that shikonin (10 μM) suppresses the expression of HIF-1α in MDA-MB-231 cells in hypoxic conditions. 188 Thus, phytochemicals inhibit cancer progression by regulating hypoxia-inducible factors by aggregation or degradation (Figure 3).

| Inhibition of oxidative stress and redox signaling
Reactive oxygen species (ROS) such as hydroxyl radical, superoxide anion radical, hydrogen peroxide, oxygen singlet, nitric oxide radical, and peroxynitrite extreme play essential roles in the initiation and development of tumors. 189 These species contribute to harmful genomic material, making them genetically unstable. Also, they act as intercessors in mitogenic and survival signaling using adhesion molecules and receptors of growth factors. Enzymes involved in an antioxidant system, such as catalase (CAT), superoxide dismutase (SOD), peroxiredoxins (PRXs), glutathione peroxidase (GPX) and glutathione reductase, are essential for maintaining cellular redox system. 190 However, it is not easy to mitigate the excessive production of ROS by cellular antioxidant enzymes. 191 It was noted that phytochemicals could modulate oxidative stress and redox signaling by regulating the expression of these enzymes. For example, Singh et al. reported protective roles of resveratrol via increasing Nrf-2 expression, which could up-regulate the expression of antioxidant genes such as SOD3, NQO1, and 8-oxoguanine DNA glycosylase 1 (OGG1). 192 In addition, biochanin A (500 μg/g) has shown anti-cancer activity in oxidative stress-mediated cancer by up-regulating CAT, DT-diaphorase, GST, GPx, and SOD, along with the reduction of lipid peroxidation and lactate dehydrogenase activities significantly. 193 Nadal-Serrano et al. reported the protective effects of Genistein on oxidative stress, redox signaling, and mitochondria, followed by upregulation of ERβ in T47D BC cells. 194 Moreover, Fan et al. reported that 3,3′-diindolylmethane (1 μmol/L) protects BC cells against oxidative stress by stimulating the expression of nuclear factor erythroid 2 in BC cells. 195 Therefore, phytochemicals regulate oxidative-mediated cancer progression by controlling potent oxidative markers, including Nrf-2 expression and antioxidant gene expression in both in vitro and in vivo models.

| Inhibition of mammosphere formation
The formation of the mammosphere is an essential characteristic of cancer progression, mainly cancer stem cells (CSCs). Several studies reported that BC cells, including non-adherent, non-differentiating CSC, form the mammosphere. 196 CSCs are believed to be associated with cancer reappearance, metastasis, and resistance to anticancer drugs. Thus, targeting breast CSCs by inhibiting mammosphere formation can be an alternative approach for managing BC. Naturally occurring plant-based compounds can prevent cancer cells and CSCs by decreasing mammosphere formation. 197 For example, Wu et al. demonstrated that pterostilbene suppressed mammosphere formation BCSCs growth by reducing CD44 + surface antigen expression and stimulating βcatenin phosphorylation. 143 The pterostilbene also modulates the hedgehog/ Akt/GSK3b signaling pathway via the down-regulation of cyclin D1 with c-Myc expression. 143 Another phytochemical, sulforaphane (SFN), reduced the number and size of ALDH1-positive (BCSC) cells, resulting in the inhibition of mammospheres formation in both in vitro and in vivo models. 198 In addition, SFN-pretreated ALDH + cells showed enhanced sensitivity to taxane, thereby blocking mammospheres formation significantly. 144 Fu et al. noted that resveratrol (100 mg/kg/day) treatment against BCSCs induces autophagy by suppressing the Wnt/β-catenin signaling pathway in MCF-7 and SUM159 cells. 146 Colacino et al. found that curcumin downregulates the expression of CD49f, ALDH1A3, PROM1, and TP6 in MCF-7, MCF10A, SUM149-derived stem cells' growth and proliferation. 147 Benzyl isothiocyanate (3 μmol BITC/g) treatment suppressed the expression of both Ron and sfRon in cultured MCF-7 derived stem cells and tumor xenografts, indicating that benzyl isothiocyanate treatment caused inhibition bCSCs in vitro and in vivo. 145 Piperine (10 μM) significantly decreased mammosphere formations in stem cells derived from BC. 199 Therefore, phytochemicals showed anti-cancer activities by inhibiting mammosphere formation in multiple breast carcinomas by suppressing signaling pathways or their components ( Figure 3).

| Inhibition of inflammation
Inflammation is a biological reaction to cellular injury produced due to infections, chronic irritation, and other inflammatory responses. 200 Information suggests that inflammatory cells, including neutrophils, macrophages, dendritic cells, eosinophils, and lymphocytes were associated with tumor formation, development, angiogenesis, and progression. 201,202 Interestingly, significant research demonstrated that natural compounds prevent inflammation by regulating antioxidant defence mechanisms via modulating Phase I, and Phase II enzymes or inflammatory cells or factors in cancer. 203 An in vitro study reported the therapeutic advantage of polyphenols on the inflammatory phenotype of macrophages. 149 In this study, supplemented pomegranate juice polyphenols reduced M1-macrophages mediated pro-inflammatory stimulation in the J774.A1 macrophage-like cells in a dose-depended manner. 149 Curcumin also exhibited anti-cancer properties against inflammation-associated carcinogenesis by inhibiting TNF-α mediated NF-κB activation and inhibiting the proteasomal activity of IκB kinase in MCF-7 cells. 150 Synergistically, using Sprague Dawley rats, curcumin with resveratrol inhibits inflammation by lowering NF-κB and reducing inflammatory markers such as COX-2 and MMP-8 expression animal model. 151 In addition, Dharmappa et al.

| Natural compounds targeting epigenetic control
Accumulating information suggests that previous studies have shown that phytochemicals can modulate the epigenetics of cancer cells by regulating the methylation of DNA via DNA methyltransferase activity and histone modifications, resulting in inhibiting the oncogenic miRNA expression and increasing tumor-suppressing miRNA expression. [213][214][215] Studies have shown that genistein could inhibit primary breast carcinogenesis by increasing some tumor suppressor protein i,e and p16, p16 (INK4a), p21, p21 (WAF1) expression, along with decreasing expression oncogene, that is, BMI1, and c-MYC in estrogen negative MDA-MB-231 cell line. 167 Moreover, genistein attributed its anti-cancer activity in BC cells by demethylating and reactivating methylation-silenced tumor suppressor genes via direct contact with inhibition of both DNA methyltransferase 1 (DNMT1) catalytic domain activation and DNMT1 expression. 213 169 Also, EGCG (15 μM) treatment is associated with epigenetic changes that can increase DNMTs transcripts expressions such as DNMT1, DNMT3a, and DNMT3b in both MCF-7 and MDA-MB-361 cells. 170 Thus, phytochemicals have the potential to modulate the epigenetic make-up of BC cells via regulating DNA methylation and histone modification; therefore, they could control the expression of oncogenes and tumor suppression genes in BC cells. The summary of phytochemicals that act against epigenetics regulation is summarized in Figure 2.

| Natural compounds targeting the immune system
Phytochemicals include substances found in nature that can be bioactive and possess an immune systemstimulating effect. 217 For example, curcumin, a clinically naturally occurring compound, has immunomodulatory properties that suppress PHA-induced T cell proliferation, IL-2, NO, and NF-κB while increasing NK cell cytotoxicity in mouse macrophage cells RAW.264.7. 218 A study involving C57BL/6 mice found that apigenin may influence the alteration of dendritic cells and other immune cell functions. 219 Daidzein, has a modulatory function on nonspecific immunity in Swiss mice when given in high doses since it enhances the phagocytic response of peritoneal macrophages. 220 Additionally, in male Kunming mice exposed to 60Coγ radiation, EGCG significantly reduced immune system destruction by inducing macrophage phagocytosis, boosting the activity of the antioxidant enzymes, that is, SOD and GSH-Px (glutathione peroxidase), raising glutathione level, and preventing lipid peroxidation. 221 Conversly, genistein regulates immunological response in female Sprague Dawley, promoting IL-4 synthesis while inhibiting IFN-γ release and balancing Th1/ Th2 cells. 222 Furthermore, kaempferol had immunesuppressive effects on cold-stressed, 6-7-week-old SPF mice, decreasing the levels of activated pro-inflammatory cytokines like IL-9 and IL-13, CD8 + T cells and raising anti-inflammatory cytokines and CD4 + T cells. 223 Therefore, selected phytochemicals have the potential to activate immune system including numerous immune cells including NK cell, CD8 + T, CD4 + T and cytokines like IL-9 and IL-13 to fight against BC cells. A summary of the anti-cancer mechanism of phytochemicals in BC treatment is presented in Table 3 and Figures 1-4.

PHYTOCHEMICALS TO ALLEVIATE THE RESISTANCE OF ANTI-CANCER DRUGS
Due to numerous significant challenges, such as multidrug resistance, treating cancer patients is becoming more difficult. 224 Drug efflux, drug inactivation, drug detoxification, drug target modification, involvement of CSCs, miRNA dysregulation, epigenetic alteration, and other numerous irregular DNA damage/repair mechanisms, tumor microenvironment, and ROS modulation are just a few potential defensive processes that could result in this resistance mechanism. 40,225,226 P glycoprotein (P-GP), MRP 1, MRP 1-9, BCRP, and changes in beta-tubulin are a few proteins that are connected to drug resistance in cancer. 227 The multi-drug resistance protein P-glycoprotein (P-gp) is overexpressed in the membrane of cancer cells, where it commonly increases drug efflux and contributes to the emergence of treatment resistance in malignancies. 228 102 The co-treatment of resistant (MCF-7R) cells with Apigenin, which reduced MDR1 expression at the mRNA and protein levels in both resistant and nonresistant cells, significantly reduced DOX resistance in the MCF-7 cell line. In both the MCF-7 and MCF-7R cell lines, apigenin strongly inhibited the phosphorylation and activation of the JAK2 and STAT3 proteins. 233 By lowering Bcl-2, Nimbolide induces the expression of the proteins Bax and caspases with a modulation of the expression of HDAC-2 and H3K27Ac, and stopping the progression of the cell cycle, as well as reduced the growth of MDA-MB-231 and MCF-7 cells. Increasing Beclin 1 and LC3B and decreasing p62 and mTOR protein expression in BC cells. Nimbolide also activated autophagy signaling. 112 Combining Sanguinarine with TRAIL therapy may break BC cells' resistance caused by overexpression of Akt or Bcl-2. In human BC MDA-231 cells, Sanguinarine triggered apoptosis, which resulted in decreased pro-caspase-3, Bcl-2, cIAP2, XIAP, and c-FLIPs protein levels and increased ROS production. 234 When Emodin was applied to the BC cells Bcap-37 and ZR-75-30, it was shown to suppress proliferation, induce apoptosis, and decrease Bcl-2 while increasing levels of cleaved caspase-3, PARP, p53, and Bax. 117 In MCF-7 and MDA-MB-231 cells, Isoliquiritigenin lowered cell survival and clonogenic potential, triggered apoptosis, suppressed mRNA expression of many AA-metabolizing enzymes, including PLA2, COX-2, and CYP-4A, and reduced production of PGE2 and 20-HETE. Moreover, it reduced the expression of phospho-PI3K, phospho-PDK, phospho-Akt, phospho-Bad, and Bcl-xL, triggering caspase cascades that ultimately led to the cleavage of PARP. 235 The expression pattern of βcatenin in BC tissue are high than the normal tissue. EGCG thus decreased the viability of MDA-MB-231 cells by lowering the levels of β-catenin, cyclin D1, and p-AKT. Moreover, pretreatment of MDA-MB-231 cells with PI3 kinase inhibitors, such wortmannin or LY294002, enhanced the suppressive effect of EGCG, given after 24 h, on the production of β-catenin. 236 By transfecting the plasmid and inducing cytotoxicity and autophagy in BCSCs derived from MCF-7 and SUM159, Resveratrol inhibits the Wnt/ βcatenin signaling pathway and excessive production of the β-catenin protein. 146 The impact of Wogonin supplementation on cell survival and proliferation has been shown to be effective against a variety of BC cell lines, including TNBC and its related cell lines, BT-549 and MDA-MB-231. Additionally, wogonin inhibits the cell cycle of cancer cell lines by inhibiting the expression of cyclin D1, cyclin B1, and CDK1, inducing apoptosis, improving the Bax/Bcl-2 ratio, and increasing caspase-3 cleavage. 237 In ER-positive BC cells like MCF-7 and T-47D cells, Calycosin tends to suppress proliferation and trigger apoptosis. This effect is caused by ER-induced inhibition of IGF-1R as well as the targeted control of the MAPK and (PI3K)/Akt pathways. 161

PROSPECTS OF PHYTOCHEMICALS IN BREAST CANCER THERAPY DEVELOPMENT
Several factors interfere with the conventional therapeutic options used to treat BC. Phytochemicals offer a broad spectrum of pharmacological effects, which might benefit the clinical management of patients with BC. Phytochemicals are an effective therapeutic agent due to their several biological properties. Though phytochemicals have enormous benefits, there are significant constraints in achieving the actual effectiveness of phytochemicalsbased therapeutic for the management of patients with BC due to the lack of systematic and proper information in this field. In addition, to develop a clinically useful drug, a series of preclinical and clinical it must pass in vitro, in vivo, and clinical trials (Phase I-IV) studies must be accomplished with clinical benefit. Furthermore, long-term studies are still required to determine therapeutic interactions, in vivo pharmacokinetic attributes, effective doses, suitable administration routes, and defined mass and/or nanoformulation of these phytochemicals. To estimate bioactivities, the structure-activity relationship must be established. Gathering additional information regarding phytochemicals' synergistic actions when combined with other phytochemicals, it is possible to boost their activity and prevent the anti-cancer profile by modifying conventional medications. Moreover, these phytochemicals could be used in computational chemistry research, such as docking, neural networking, and pharmacophore-based virtual screening programs for the drug development sector. Therefore, these phytochemicals could potentially become a potent chemotherapeutic anti-cancerous substance in managing BCs, at least at the cellular level and could be formulated for clinical applications if all of the strategies are accomplished.

FUNDING INFORMATION
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.