Table 1.

Summary of activities of natural compounds in breast cancer treatment and management.

Chemical compound	Structure	Major source	Mechanisms	Remarks	References
3,3′-Diindolylmethane		Broccoli, cauliflower, cabbage	Arachidonic acid pathway	(i) Inhibits COX-2 expression in MCF-7 breast cancer cells	[83]
			Apoptosis pathway	(i) Downregulates survivin, Bcl-2, and cdc25A (ii) Upregulates p21(WAF1) expression	[84]
			HIF-1 signaling pathway	(i) Decreases the expression of key hypoxia responsive factors, VEGF, furin, enolase-1, glucose transporter-1, and phosphofructokinase in hypoxic tumor cell lines	[85]
			Aromatase activity	(i) Inhibits aromatase expression	[86]
			Chemosensitivity/ adjuvant therapy	(i) Increases the efficacy of herceptin by reducing FoxM1, Akt, and NF-κB p65 level   (ii) Increases the chemosensitivity of tamoxifen and alter the estrogen metabolism in randomized, placebo-controlled trial (iii) Sensitizes MDR human breast carcinoma to γ-irradiation	[87–89]
Biochanin A		Red clover	Aromatase activity	(i) Inhibits aromatase expression	[90]
			Cytoplasmic signaling pathways	(i) Inhibits HER-2 receptor activation (ii) Inhibits Erk1/2, Akt, mTOR, NF-κB, MMP-9, and MT-MMP1	[91]
				(i) Inhibits tumor growth in a xenograft animal model at dose of 15 mg/kg	[92]
Curcumin		Turmeric	Apoptosis pathway	(i) Increases p53 level (ii) Increases Bax expression (iii) Downregulates NF-kappaB, cyclin D, and MMP-1 transcription in MDA-MB-231 and BT-483 cell line	[93]
			Wnt signaling pathway	(i) Inhibits Wnt signaling at a dose of 5 μM in MCF-7 cell line	[94]
			Epigenetic regulation	(i) Inhibits the expression of class I HDACs (ii) Upregulates the expression of some miRNAs to reduce the expression of Bcl-2	[95, 96]
			Chemosensitivity/ adjuvant therapy	(i) Enhances the efficacy of paclitaxel by deactivating NF-κB and MMP-9 expressions in MDA-MB-231 cell (ii) Inhibits the efflux function of P-gp, MXR, and MRP1 in MCF-7 and MCF-7MDR cell line	[97, 98]
Emodin		Rhubarb, buckthorn	Apoptosis pathway	(i) Inhibits HER-2/neu tyrosine kinase activity in HER-2/neu-overexpressing cancer cells	[99]
Epigallocatechin gallate		Green tea	Epigenetic regulation	(i) Decreases 5-methylcytosine, DNA methyltransferase (DNMT) activity, DNMT1, DNMT3a, and DNMT3b (ii) Decreases histone deacetylase activity (iii) Increases levels of acetylated lysine 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysine 5, 12, and 16 on histone H4 (iv) Decreases the levels of methylated H3-Lys 9. (v) Increases the expression of p16INK4a and Cip1/p21. (vi) Induces the expression of epigenetically repressed TIMP-3 gene	[100–102]
			Apoptosis pathway	(i) Decreases aryl hydrocarbon- (AhR-) regulated genes (ii) Blocks ERβ-specific inhibitor PHTPP (iii) Decreases the expression of Bcl-2 but increases Bax (iv) Increases release of cytochrome c (v) Increases the expression of Apaf-1 (vi) Activates of caspase-3 and poly(ADP-ribose) polymerase (vii) Alters the EGFR activity (viii) Increases the expression of p21 and p27, caspase-3, caspase-8, and caspase-9 and TP53	[103–111]
			Arachidonic acid pathway	(i) Decreases the COX-2 expression and kappaB (NF-kappaB) activations	[112, 113]
			Chemosensitivity/ adjuvant therapy	(i) Increases the sensitivity of ionizing radiation (ii) Increases the bioavailability of tamoxifen, 5-fluorouracil, and doxorubicin	[114–117]
Genistein		Soy products	Arachidonic acid pathway	(i) Inhibits COX-2 expression (ii) Regulates PGE2 (iii) Inhibits sPLA2, NF-κB, and ERK mediated phosphorylation of p65 in breast cancer cell (iv) Activates both ERα and ERβ	[118–122]
			Apoptosis pathway	(i) Upregulation of Bax and p21WAF1 protein in MDA-MB-231 cell lines (ii) Downregulation of caspase-3 (iii) Regulates calpain-caspase-7 and 1-p38 mitogen-activated protein kinase activation cascades (iv) Inactivates the IGF-1R-PI3K/Akt pathway and reducing the Bcl-2/Bax (v) Enhances G2/M arrest by activating the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway	[123–127]
			Epigenetic regulation	(i) Regulates the p21 and p16 expression (ii) Epigenetically restores ERα expression (iii) Blocks the expression of DNMT1	[128, 129].
				(i) Uprises the regulation of Brca1 and Brca2 mRNA expressions in adult ovariectomised rats (ii) Reduces the size of the tumours by 50%	[130]
Lycopene		Tomato, carrot, watermelon, papaya, cherry	Epigenetic regulation	(i) Upregulated the expression of GSTP1 (ii) Demethylates GSTP1 promoter	[131]
			Apoptosis pathway	(i) Blocks the phosphorylation of Akt downstream pathway (ii) Upregulates the proapoptotic Bax without affecting antiapoptotic Bcl-xL (iii) Suppresses cyclin D1 and upregulates p21 (iv) Sustains the activation of the ERK1/2 (v) Increases the expression of p53 and Bax	[132, 133].
Sulforaphane		Broccoli, water crass, boccoli sprouts, cabbage, kale	Epigenetic regulation	(i) Inhibits hTERT (human telomerase reverse transcriptase)	[134]
			Apoptosis pathway	(i) Increases the expression cyclin B1 (ii) Activates the poly(ADP-ribose) polymerase 1 and caspase family proteins (iii) Inhibits tubulin polymerization (iv) Downregulates the nuclear factor kappa B signaling pathway (v) Decreases the expressions of Bcl-2 and phosphorylated Akt serine/threonine kinase	[134–136]
			Chemosensitivity/ adjuvant therapy	(i) Increases chemosensitivity of paclitaxel in breast cancer cells (ii) Enhances the sensitivity of tamoxifen by epigenetic reactivation of ERα in ERα-negative breast cancer	[137–139]
			Arachidonic acid pathway	(i) Inhibits the expression of nuclear factor kappa B (ii) Blocks COX-2 expression, which is mediated by ERK1/2-IKK-α and NAK-IKK- β	[140, 141]
				(i) Decreases the expressions of SOX9 and ALDH1 in vivo (ii) Decreases ALDH+ and downregulates the Wnt/β-catenin self-renewal pathways in NOD/SCID xenograft model at a dose of 50 mg/kg for 2 weeks	[141, 142]
Shikonin		Lithospermum erythrorhizon	Estrogen signaling	(i) Activates ER ubiquitination (ii) Inhibits pS2 and c-myc, estrogen responsive gene promoters (iii) Induces DNA damage by triggering the Nrf2 pathway	[143, 144]
			Apoptosis pathway	(i) Decreases the expressions of steroid sulfatase genes (ii) Activates caspase-3 (iii) Suppresses NF-κB pathway, Bcl-2, and Bax (iv) Downregulates p65 and inhibition of IκB-α phosphorylation	[145, 146]
			Chemosensitivity/ adjuvant therapy	(i) Increases the chemosensitivity of taxol in ER negative human breast cells (ii) Induces cell cycle arrest at the G2/M phase and inhibits the activation of ERK, Akt, and p70S6 kinases (iii) Decreases tamoxifen resistance by inducing uc.57 and downregulates BCL11A	[147, 148]
Silibinin		Milk thistle	Apoptosis pathway	(i) Induces autophagic cell death by downregulating the Bcl-2 expression (ii) Upregulates Atg12-Atg5 formation and enhances beclin-1 expression	[149]
			Arachidonic acid pathway	(i) Suppresses Wnt/LRP6 signaling (ii) Downregulates the TPA-induced MMP-9 expression and inhibits COX-2 expression in breast cancer cells	[150, 151]
			Chemosensitivity/ adjuvant therapy	(i) Increases the efficacy of cisplatin and paclitaxel	[152, 153].
Resveratrol		Grapes	Epigenetic regulation	(i) Inhibits DNMT 3b expression and decreases RASSF-1α methylation (ii) Activates SIRT1 and acetyl transferase p300 (iii) Decreases the expressions of DNMT1, DNMT3a, and DNMT3b, HDAC1, and methyl CpG binding protein 2 (MeCP2) in MCF-7 cell line	[154–157]
			Arachidonic acid pathway	(i) Inhibits ERβ, COX-2, NQO2, IKK, and GSTP1	[158, 159]
			Aromatase activity	(i) Reduces aromatase mRNA expression (ii) Suppresses the transactivation of CYP19 promoters I.3 and II	[160]
				(i) Consumption of 1 g resveratrol per day had complimentary effects on estrogen metabolism as well as sex steroid hormone binding globulin in postmenopausal women having high body mass index	[161]
			Apoptosis pathway	(i) Stimulates p53-dependent pathway at a low dose in MCF-7 cells (ii) Suppresses ER- dependent PI3K pathway (iii) Src tyrosine kinase and signal transducer and activator of transcription 3 (STAT-3) phosphorylation pathways (iv) Reduces Akt phosphorylation and activates of procaspase-9 (v) Activates mitochondrial protein (Smac/DIABLO), caspase-9, and caspase-3	[162–165]
Rosmarinic acid		Rosemary	Arachidonic acid pathway	(i) Reduces the COX-2 expression, AP-1 activation, and antagonized the ERK1/2 activation (ii) Suppresses interleukin-8 (IL-8) in the pathway of the NF-κB	[166, 167]
Rutin (quercetin 3-O-β-d-rutinoside)		Buckwheat	Chemosensitivity/ adjuvant therapy	(i) Restores the chemosensitivity in HER2-negative and triple-negative breast cancer cell lines (ii) Reduces c-Met kinase activity in TNBC cell line and also significantly reduces the growth of TNBC MDA-MB-231/GFP orthotopic xenograft in nude mouse model at a dose of 30 mg/kg	[168, 169]