Table 1.
Potential anticarcinogenic roles of phytochemicals in regard to breast cancer.
| Bioactive Dietary Compounds | Food Sources | In Vitro and In Vivo Models | Effects on Molecular Biomarkers/Signaling Pathways | Effects on Biopathological Processes | Role in BC |
|---|---|---|---|---|---|
| Sulforaphane | Organo-sulfur compound obtained from broccoli/broccoli sprouts, kale, cabbage, cauliflower, garden cress, mustard [112,113] | MDA-MB-231 and MDA-MB-157 [116] | Targets MAPK/ERK [116]; downregulates NF-κB, AKT, and KEAP1; affects histone deacetylases involved in chromatin remodeling, and NRF2 antioxidant signaling [113] | Inhibits cell proliferation; causes apoptosis and cell cycle arrest; has antioxidant activities [113]; suppresses TGF-β1-induced migration, invasion, and metastasis of TNBC cells [116] | Chemoprotective [116], putative potential for BC treatment [113] |
| Allicin | Organo-sulfur compound from garlic (Allium sativum) [119] | MCF7 and HCC-70 [155], MCF7 and MDA-MB-231 [120] | Downregulates caspase 3/8/9 and Bcl-XL; upregulates NOXA, p21, and BAK expression [155]; induces p53 activation [120] | Decreases BC cell proliferation and viability and increases apoptosis, induces cell cycle arrest [120,155], improves DOX sensitivity [118] | Antitumor [155] |
| Quercetin | Flavonoid from fruits, vegetables (cruciferous vegetables, grapes, apples, tomatoes, blueberries), and herbal products (Hypericum perforatum, Sambucus nigra) [156] | 4T1 and xenograft mouse model [125]; MCF-7 and MDA-MB-231 [124] | Suppresses IL-6/JAK2/STAT3 pathway [125], modulates the expression of caspase-3/8/9 [124] | Suppresses TNBC progression (proliferation, migration, and invasion) [125], induces apoptosis [124] | Potential anti-BC agent [124]; potential adjuvant for immune therapy in TNBC [125] |
| Luteolin/luteolol/ digitoflavone |
Flavonoid from carrots, broccoli, celery, perilla mint leaves and seeds, apple skin, cabbages, parsley, onion leaves, thyme [157,158,159] | MDA-MB-231, BT549, and mouse model [157]; MDA-MB-231, MDA-MB-486, 4T1, BT549 [158]; MDA-MB-453 and MCF7 [160] |
Reverses EMT through the suppression of β-catenin and VIM; stimulates E-cadherin and claudin; downregulates N-cadherin, Snail, and Slug; reorganizes F-actin [157]; inactivates AKT/mTOR and downregulates MMP9 through H3K27Ac and H3K56Ac [158]; upregulates miR-203, inhibits Ras/Raf/MEK/ERK, downregulates Bcl-2, upregulates Bax, impedes TGFβ1-induced EMT, decreases VIM, ZEB1, and N-cadherin, and increases E-cadherin [160] |
Inhibits migration and invasion of TNBC cells [157], inhibits proliferation and metastasis, and promotes apoptosis of AR+ TNBC cells [158] | Chemopreventive and potential therapeutic agent for TNBC [157], including AR+ TNBC [158] |
| Hesperetin | Flavanone glycoside from Citrus fruits (oranges and lemons) [161] | MDA-MB-231 [161]; MCF7, including mammospheres [162,163,164] | Inhibits the Fyn/paxillin/RhoA signalling pathway [161]; activates the ASK1/JNK pathway, initiates the accumulation of ROS [162]; modulates the expression of p53, PPARG, and Notch1 [163]; downregulates CDK2/4 and cyclins, and upregulates p21Cip1 and p27Kip1, stimulates the binding of CDK4 to p21Cip1 [164] |
Inhibits the migration and invasion induced by TGF-β1 [161]; exerts cytotoxic and proapoptotic effects [162]; inhibits BCSCs, exerts cytotoxicity on mammospheres, inhibits mammospheres, colony formation and migration, modulates cell cycle and induces apoptosis [163]; suppresses proliferation and stops the cell cycle in G1 [164] |
Potential anti-BC agent, especially for TNBC [161] |
| Hesperidin | Flavanone from citrus fruits [165] | MCF7 cells [165], MDA-MB-231 [166], mammospheres [167], MDA-MB-231 [168], Wistar rats [169] |
Suppresses AKT and NF-kB signalling, inhibits PD-L1 [166], increases p53 [167], binds to MCL-1 receptor [168], attenuates Ki67 [169] | Suppresses cell proliferation [165], inhibits cell migration and growth [166], suppresses mammospheres and colony formation, induces apoptosis [167], exerts cytotoxic effects [168] |
Anti-BC activity [165,167], protective against DMBA-induced BC [169] |
| Naringenin | Flavanone glycoside from grapefruits, apples, onions, tea [170,171] | MDA-MB-231, Wistar rats induced with BC by DMBA [170], C57BL/6J mice induced with BC through a transplant of E0771 cells [172], Balb/c mice induced with BC through a transplant of transduced 4T1-Luc2 cells [173], MCF-7 [174] |
Modulates mitochondrial-mediated pathway, upregulates caspase-3/7 [170], increases AMPK, decreases cyclin D1 [172], inhibits PKC, inhibits secretion of TGF-β1, causing its intracellular accumulation [173], inhibits PI3K and MAPK [174] |
Inhibits cell proliferation and cell cycle, induces apoptosis, reduces the incidence of BC tumors [170], decreases cell viability in vivo, suppresses cell cycle progression [172], inhibits lung metastasis, increasing the survival rates of the mice [172], suppresses proliferation, impairs glucose uptake [174] |
Antineoplastic agent [170], putative therapeutic option for TGF-β1 modulation [173], antiproliferative agent [174] |
| Naringin | Flavanone glycoside from tomatoes, grapefruits, and other Citrus fruits [175] | MDA-MB-231, MDA-MB-468, BT-549 [175] | Increases p21, decreases survivin/BIRC5, suppresses β-catenin pathway [176] | Inhibits cell proliferation, stimulates apoptosis [176] | Potential treatment agent for BC [176] |
| Apigenin | Flavone from parsley, onions, chamomile, oranges, wheat sprouts [177], celery, green peppers [178], thyme [179] | MDA-MB-453 and BT-474 [177], SK-BR-3 [177,178], MCF-7 [177,180], HBL-100 [177], MCF7-T, MCF7-F [179], MDA-MB-231, A549, SK-Hep1, nude mice [181] | Depletes HER2/neu and disrupts HER2/neu-GRP94 complex [177], modulates CDK1, p21Cip1, and p53 [178], induces degradation of ERα and AIB1 [179], blocks PI3K/AKT pathway [177,181] and β4 integrin function, inhibits pAKT, inhibits cell motility, migration, and invasion [181], inhibits AKT/FOXM pathway, suppresses FOXM1, and modulates ER signalling [180] | Suppresses BC cell growth, induces apoptosis [177], inhibits proliferation [180], ref. [177], activates p53-induced apoptosis [177], inhibits growth of ERα+ BC cells [179], inhibits metastasis [181] | Potential anticancer treatment [177] |
| Tangeretin | Flavone from lemons, oranges [182], other Citrus fruits [183] | MCF7, MDA-MB-468, MDA-MB-231, nude mice injected with MDA-MB-231 cells [182,184], Sprague-Dawley rats induced with DMBA [185], Wistar rats induced with DMBA [183] | Inhibits STAT3 and SOX2 pathways, decreases STAT3-DNA binding, reduces STAT3 in BCSCs [182], induces CYP1A1/CYP1B1 activity [184], decreases ROS and pro-inflammatory factors, protects against LPO [185], upregulates p53/p21, suppresses MMP2/9 and VEGF, reduces PCNA and COX2 [183] | Inhibits proliferation [182,183,184] and metastasis [183], inhibits BCSC formation, induces apoptosis, inhibits mammospheres and colony formation [182], decreases tumorigenicity and OS levels, boosts antioxidant levels [185] | Anti-BC effects |
| Daidzein | Isoflavone from fruits, nuts, soy beans and soy-based products [85] | MCF-7 [85,86,186], MDA-MB-453 [85], T47D [186], MCF-10DCIS [87] |
Induces cell cycle arrest, inhibits cyclin D, CDK2/4, increases p21Cip1 and p57Kip2 expression, increases caspase-9 activity [85]; generates ROS, disrupts mitochondrial function [86]; inhibits TNF-α and suppresses hedgehog/Gli1 signalling [87]; upregulates Bax and downregulates Bcl-2, induces apoptosis and lowers ERα/β ratio and ROS outbursts [88] |
Inhibits cell proliferation, induces apoptosis [85,86]; inhibits migration and invasion [87] | Anti-BC potential [88] |
| Genistein | Phytoestrogenic soy (Glycine max)-derived compound [81] from soy nuts, soy powder, soy milk, tofu, miso, natto [187], lupin, fava beans, kudzu, and psoralea [80]; exerts tyrosine kinase-modulating activities [84] |
MCF-7 [79,81,82]; MCF7 and MDA-MB-435 transfected with human HER2 [84]; PDX mouse models for TNBC [80] | Suppresses IGF-1R/p-AKT and decreases Bcl-2/Bax [81]; downregulates NF-κB/Bcl-xL/TAp63, influences key epigenetic associated genes, genomic DNA, and histone methylation [80]; upregulates PI3K and MAPK signalling, downregulates p27 Kip1 levels in ER+/HER2+ BC cells [84] | High concentrations kill MCF7 BC cells [79] or delay TNBC tumor growth [80]; inhibits proliferation/differentiation, induces apoptosis [81,82]; inhibits angiogenesis [83]; induces tamoxifen resistance and growth in ER+/HER2+ BC cells and inhibits growth of ER-/HER2+ BC cells [84] | Exhibits anticancer effects on various cancers [188]; chemoprevention in terms of BC carcinogenesis is concentration-, exposure time-, and BC subtype-dependent |
| Genistin | A glucoside form of genistein, readily absorbed in the intestine, found in soy beans and soy-derived foods, some legumes, and vegetables [187,189] |
MCF-7, MDA-MB-231 [189] |
Docks to ERα, ERβ, lowers CA 15-3 levels [190]; induces negative regulation of ERα signalling pathway, suppresses expression of oncogenic biomarkers [189] | Stimulates cell cycle arrest and apoptosis, reduces BC cell growth, proliferation, and angiogenesis [189] | Chemoprevention and therapy in terms of ER+ BCs [189]; useful for potential new drug discovery for BC management and treatment [190] |
| Lycopene | Major carotenoid found in tomatoes, red fruits, red carrots, watermelons, grapefruits, papayas [127] | MCF7, SK-BR-3, MDA-MB-468 [129] |
Inhibits pAKT and mTOR signalling pathways, upregulates Bax [129] | Inhibits cell proliferation and cell cycle progression, initiates apoptosis [128] | Chemopreventive for TNBC [129] |
| Gallic acid | Hydroxybenzoic acid in fruits, vegetables, medicinal plants, such as grapes, gallnuts, pomegranates, hawthorn, tea leaves, capers [191,192,193], honey [194] | MCF7 [191], HCC1806 [195], MDA-MB-231 [196] | Suppresses PI3K/AKT/EGFR, nuclear accumulation of β-catenin [191,195], activates mitochondrial apoptosis pathways [195] | Inhibits survival of acidity-adapted BC cells and reduces metastatic characteristics induced by acidity [191], suppresses proliferation, promotes apoptosis [195] and ferroptosis [196] | Promising therapeutic agent for metastatic BC [191], antioxidant [193], suppresses TNBC progression [195] |
| Vanillic acid | Hydroxybenzoic acid in medicinal plants (e.g., Angelica sinensis), olives, cereals, whole grains, fruits, green tea, juices, berries, wines [197] | MCF7 [198] | Affects ROS pathway [198] | Generates ROS, promotes apoptosis [198] | Antiproliferative effects [198] |
| Protocatechuic acid | Hydroxybenzoic acid in olives (Olea europaea)/olive oil, hibiscus, white grape (Vitis vinifera) wine [199], purple rice bran extract [200], edible mushrooms (Hydnum repandum) [201], potatoes, onions, wheat [202] | MCF7 [199] | Reduces IL-6, IL-8, and suppresses VEGF [199] | Induces apoptosis and limits invasion and metastasis [199] | Potent anticancer agent [199], antioxidant [202] |
| Syringic acid | Hydroxybenzoic acid from olive oil, dates, grapes [203], foxtail millet bran (Setaria italica) [204] | MCF7, MDA-MB-231 [204] |
Downregulates GRP78/SERBP-1/SCD1 signalling axis [204] | Antiproliferative activities [203,204] | Anti-BC agent [204], antioxidant [203] |
| Ellagic acid | Hydroxybenzoic acid from fruits, seeds, nuts, pomegranates, raspberries, strawberries, black raspberries, almonds, and walnuts [205] | MCF7 [205] | Regulates TGF-β/SMAD3 signalling axis, inhibits CDK6, binds to ACTN4 and induces its degradation via ubiquitin–proteasome pathway, reduces VEGFR-2 [205] | Suppresses BC cell growth, migration, invasion, metastasis, stimulates apoptosis, inhibits angiogenesis [205] | Anti-BC activities [205] |
| Caffeic acid | Hydroxycinnamic acid from fruits, green and roasted coffee, vegetables, tea, oils, spices [206,207], honey, and propolis extracts [194,208] | MCF7 [206] | Stimulates p53 and p21 genes, inhibits CDK2 [206], inhibits DNA methylation [208] | Induces apoptosis, cytotoxic effects, morphological changes in BC cells [206] | Putative antitumor agent [206] |
| Cinnamic acid | Hydroxycinnamic acid from cinnamon, grapes, tea, cocoa, spinach, celery [209] | MDA-MB-231, HEK293 [209] | Increases TNF-α-TNFR1 apoptotic pathway and caspases 8/3 [209] | Increases apoptosis and DNA damage [209] | Anti-BC agent [209] |
| p-Coumaric acid | Hydroxycinnamic acid from whole cereal grains, fruit, vegetables, Brazilian green propolis extracts [210] | MCF7 [210], BT20, BT549, MDA-MB-231, MDA-MB-436 TNBC [208] | Inhibits iNOS, COX-2, IL-1β, TNF-α, suppresses p-IκB, ERK1/2, blocks NF-κB and MAPKs pathways [211] | Reduces cell viability/cytotoxic effects, reverts the epigenetic silencing of the tumor suppressor RASSF1A [208], supports anti-inflammatory and immunomodulatory mechanisms [211] | Putative antiproliferative/anticancer agent [210,212] |
| Ferulic acid | Hydroxycinnamic acid from plants: ferulic (Ferula foetida), angelica, jujube kernel, rice bran, wheat bran [213], nuts, seeds [214] | MDA-MB-231 [215], MCF7 [216] | Regulates EMT [215] | Decreases viability and proliferation, increases apoptosis via activation of caspase-8 and -9, suppresses migration and metastasis [215,216] | Antitumor agent [215], antioxidant agent that protects DNA from OS [214,217] |
| Sinapic acid | Hydroxycinnamic acid from citrus fruits (oranges, grapefruits, lemons), berries; herbs (canola, mustard seed, rapeseed); cereals, wheat, rice, spices, oil seeds, vegetables, vinegar, Salvia officinalis, Myristica fragrans [218] | MCF7, T47D, MDA-MB-468, SK-BR-3 [219] | Downregulation of VKORC1 and KIF18B [219] | Induces apoptosis [219] | Cytotoxic agent in regard to luminal A BC cell lines [219] |
| Rosmarinic acid | Hydroxycinnamic acid from medicinal plants, herbs, spices (Boraginaceae, Lamiaceae, Labiatae) [220] | MDA-MB-231, MDA-MB-468 TNBC [220] | Upregulates TNF, GADD45A, BNIP3, HRK, TNFRSF25, inhibits BIRC5/survivin, MARK4, hedgehog pathway and hippo signalling, decreases proliferation and migration via Bcl-2/BAX signalling pathway, inhibits NF-κB signalling [220,221] | Antiproliferation and migration/cell cycle arrest, apoptosis [220] |
Anti-BC agent, antioxidant [220] |
| Chlorogenic acid | Hydroxycinnamic acid from fruits (apples, plums), vegetables (potatoes, eggplants), olive oil, spices, wine, coffee beans [222,223,224], honey [194] | Subcutaneous tumor mouse model of 4T1 cells [222] | Inhibits NF-κB/EMT signalling pathways [222] | Induces apoptosis, inhibits pulmonary metastasis, and improves anti-BC immunity [222] | Potential candidate for therapy of BC [222] |
| Avenanthramides (AVN-A, B, C) | Phenolic alkaloids found in oats (Avena sativa, Poaceae) [225] | MDA-MB-231 [226] | Activates caspase 3/7 [226] | Activates apoptosis and senescence, blocks cell proliferation, inhibits EMT and metastasis [225] | Anticancer effects [225] |
| Cyanidins/cyanidin 3-O-glucoside | Water-soluble anthocyanins found in leaves, petals, flowers, red fruits, blackberries, cranberries, grapes, cherries, apples, raspberries, peaches, plums, beans, red cabbage, red onions, purple sweet potatoes, carrots, avocadoes, olives [227,228] | BT474, MDA-MB-231, MCF7 [228,229] | Increases the expression of p53, Bax, caspase 3, CYP1, CYP2, and decreases Bcl2 [228], blocks ERBB2/cSRC/FAK pathway [229] | Proapoptotic and cytotoxic effects [228], inhibits invasion and metastasis [230], anti-mutagenic and anticarcinogenic effects [231] | Anticancer agent [228] |
| Delphinidin | Polyphenolic natural pigment occurring in berries, eggplant, wine [232] | MDA-MB-231, BT474 [233] | Induces protective autophagy via suppression of mTOR and activation of AMPK pathway in HER2+ BC cells [233] | Inhibits proliferation [108], promotes apoptosis and autophagy [233], exerts anti-mutagenic and anticarcinogenic effects [231] |
Anticancer effects [233], antioxidant [232] |
| Malvidin/ malvidin-3-O-glucoside |
Abundant anthocyanin in red wine, red grapes (Vitis vinifera), the skin of colored fruits, blueberries (Vaccinium corymbosum), blackberries (Rubus sp.) bilberries (Vaccinium myrtillus), red raspberries (Rubus idaeus), black raspberries (Rubus occidentalis), cranberries (Vaccinium macrocarpon), strawberries (Fragaria ananassa) [234] | MCF7 | Increases p21, caspases 3/8/9, Bax/Bcl-2, inhibits NF-κB, PI3K, TNF-α, STAT3, MMP2/9, IL-6, WNT, Notch1, and cyclin D1 [234] | Induces cell cycle arrest, antioxidation, anti-inflammation, autophagy, and apoptosis; inhibits proliferation, metastasis/cell invasion [234] | Anticarcinogenic potential [234] |
| Peonidin | Anthocyanidin found in purple sweet potatoes (Ipomoea batatas) [235], pigmented rice (red, black, dark purple) [230] | In silico [235] | Inhibits the overexpression of HER2 protein [235] | Proapoptotic, antiproliferative, anti-metastasis role [230] | Anti-BC activity [235] |
| Resveratrol | Non-flavonoid polyphenol from blueberries, grapes, red wine, raspberries, mulberries, apples, pomegranates, soy beans, peanuts | MDA-MB-231 [135] | Modulates PI3K/AKT, NF-κB, and Notch signalling pathways [133,134] | Induces Bax-dependent, but p53-independent, apoptosis [135] | Chemopreventive and putative therapeutic agent [236] |
| Curcumin | Polyphenol derived from turmeric (Curcuma longa) | MCF7 [137,138], MDA-MB-231, and Hs 578T [147] | Modulates NF-κB [137]; downregulates oncogenic RAF-1, suppresses telomerase, upregulates TNF-α and IL-8 genes [138]; inhibits EMT through downregulation of mTOR and PI3K/AKT signaling [147] | Inhibits cell stemness [148], proliferation, and promotes apoptosis [137]; suppresses motility and metastasis in TNBC [147] | Chemopreventive agent [137], anticancer and cytotoxic properties [138]; potential therapeutic agent [147] |
| Epicatechin | Flavan-3-ol from green tea, cocoa, grapes, apricots, green algae [237] | 4T1 [237], [238], TNBC mice model [150], MCF-7 [239] [240], MDA-MB-468 [153], MDA-MB-231 [240] |
Increases Bax/Bcl-2 ratio, increases the expression of CDH1, MTSS1, PTEN, BMRS, FAT1, and SMAD4 [237], modulates the AMPK and Akt/mTOR pathways [238] |
Decreases cell growth [150,238], inhibits metastasis-associated proliferation, reduces migration [150], cytostatic effects at lower concentrations [239], inhibits proliferation [238], proapoptotic [153,240] | Antiproliferative agent, similar effects to doxorubicin in terms of tumor growth inhibition and survival rates [238], could be used as an inhibitor for BC progression (anti-metastatic, anti-migratory, anti-invasion) [150] |
| Catechins | Flavan-3-ols found in black grapes, strawberries, cider, red algae, green algae, red wines, kiwis, green tea, gooseberries [241,242] | 4T1 [241] | Downregulates EGFR, APP, Bcl-2, DNMT, HIF1a, and PSMB5; upregulates caspase 3 and GADD45b [241] | Suppresses proliferation, stimulates apoptosis [241] | Antiproliferative agent [241,242] |
| Epigallocatechin gallate | Flavan-3-ol from green and black tea, apples, cherries, red algae, other fruits and vegetables [151,208,242] | BT20, BT549, MDA-MB-436, MDA-MB-231, MCF7, T47D, Hs 578T, allograft Balb/c model [151,208] |
Downregulates mTOR, PI3K/AKT, p53/Bcl-2, EGFR, VEGF, STAT3, NF-κB, SCUBE2, TIMP3, DNMT, ERα; activates JNK, caspases 9/3 [151,208] | Decreases cell growth, increases apoptosis, prevents DNA damage and proliferation, inhibits invasion, reduces cell viability, has cytotoxic effects [208] | Antiproliferative and anti-invasion agent, hypomethylating agent [208] |
| Theaflavin | Antioxidant polyphenol found in black tea [152,243] |
T47D, MDA-MB-231 [244], MCF-7, ZR-75-1 [245] |
Upregulates Fas/caspase 8, downregulates pAKT/pBAD pathway [244]; increases p53, Bax, activates caspase 6/7/9, increases ROS, stimulates p53, downregulates MMP2 and MMP9, inhibits the translocation of NF-kB/p65 to the nucleus [245] | Induces apoptosis [244], probably in a p-53-dependent manner [152], reduces cell viability, inhibits cell migration, could induce p53 phosphorylation of the Ser15 residue [245] | Proapoptotic agent [244] |
| Theaflavin-3-gallate | Polyphenol from fruits and veggies | MCF-7, MCF-10A [246] | Downregulates HSP90, MMP9, VEGFA, and SPP1 genes [246] | Inhibits cell proliferation, no cytotoxic effects on non-malignant breast cells (MCF-10A), induces apoptosis by stopping the cell cycle in the G2/M phase, decreases migration and colony formation [246] | Potentiate other BC therapies [246] |
| Phlorizin | Bioactive chalcone found in Asteraceae, Ericaceae, Saxifragaceae, Proteaceae, Rosaceae, Rutaceae, Fabaceae, Lamiaceae, Plantaginaceae, Pyrus communis [247] | MDA-MB-231, T47D [248], MCF7 [249] | Inhibits ERα signalling pathway, increases apoptotic caspase 3 via p53 [249] | Stimulates apoptosis, induces cytotoxicity/genotoxicity [248,249], antioxidant, anti-inflammatory, affects the composition of gut microbiota and development [250] | Anti-BC potential [247] |
| Kaempferol | Flavonoid from plants, fruits, vegetables, onions, apples, berries, tea [124,251] | MCF7 [252,253,254], MDA-MB-231, xenograft models [124,255] | Suppresses cyclin D1, p21, TWIST, and p38 MAPK [252], downregulates SNAI2, PLAU, CSF1, inhibits IGF1/IGF1R-mediated EMT [255] | Induces apoptosis, inhibits growth, migration, and proliferation of BC cells [124,252,256] | Anticancer effects [124,252], potentiates sensitivity to chemotherapy drugs [253,254] |