Table 2.

Natural substances from plants/fungus indicated in TNBC treatment. Natural compounds mitigate tumor growth by modulating different cell signaling pathways. This table provides an overview of the selected compounds, their potential targets, the signaling pathways involved and experimental models used. Also included is Asparagine, an amino acid and natural compound with pro-carcinogenic effect in TNBCs. Certain non-TNBC cell line (such as MCF-7, T47D, SKBR3 and BT474) related studies have also been mentioned in the table. While the MCF-7 and T47D cells express both the estrogen receptor (ER) and progesterone receptor (PR), the SKBR3 cells express only the human epidermal growth factor receptor 2 (HER2) and are devoid of ER or PR. On the other hand, the BT474 cells express all the three (ER, PR and HER2) receptors. Breast cancers devoid of these three receptors are classified as TNBCs (MDA-MB-231, MDA-Mb-468, MDA-MB-435, BT20, SUM149PT, SUM159PT). LM2-4175 cells indicate MDA-MB-231 TNBC cells derived from lung metastatic sites. 4T1 is a breast cancer cell line derived from the tumors of the mammary glands of mice.

Compound	Chemistry	Source	Conditions Used for	In Vitro	In Vivo	Targets/Markers	Signaling
Natural Compounds: Having Anti-Cancer Properties in TNBC and Non-TNBC Cell Lines
(A) Luteolin	Flavonoid (Figure 2A)	Broccoli, Green chilli, Onion leaves, Carrot, Radish, Celery [168]	Hypertension, inflammatory disorders and cancer [156]	MDA-MB-231, LM2-4175, MDA-MB-435, BT-549	Xenograft	Vimentin, Snail, Slug β-catenin [162] VEGFR2 [161] MMP-2/9 Notch-1, Hes-1, Cyclin D1	PI3K/Akt, MAPK/ERK1/2, STAT3 [169] Notch [164]
(B) Chalcones	Flavonoid (Figure 2B)	Tomatoes, Shallots, Beans, Citrus, Apples	Asthma, gastric ulcer, skin diseases, parasitic infections [170]	MDA-MB-231, BT-549, MDA-MB-468	MDA-MB 231/4mRL.luc2 (SCID) mice	Cell cycle, NF-κB, p65, p38, Hsp90 [171], Wnt/β-catenin, Bcl2 [172]	Wnt/β-catenin, VEGF/VEGFR2
(C) Piperine	Alkaloid (Figure 2C)	Pepper	Pain, chills, fever, reduces blood cholesterol	MDA-MB-231, MDA-MB-468, T47D, MCF-7	MDA-MB-468 (NOD/SCID), 4T1-luc mouse TNBC	TRAIL, MMP 2 and 9 [173], survivin, p65 [174], cell cycle components	ERK1/2, p38 MAPK and Akt [175]
(D) Deguelin	Flavonoid (rotenoid) (Figure 2D)	Natural insecticides	Insecticide piscicide	BT474, T47D, MDA-MB-231, BT-549, BT20, MCF-7	MDA-MB-231 (athymic-mouse)	β-catenin, cyclin D1, XIAP, survivin, EGFR and c-Met	EGFR [176]
(E) Quercetin (F) Rutin	Flavonoid (Figure 2E) (Figure 2F)	Apples, Onions	Cardio-vascular, common cold, allergy	MDA-MB-157, MDA-MB-231, MDA-MB-468,	C3(1)/SV40Tag transgenic mouse	β-catenin, Foxo3A FASN [177] c-Met, p51, p21 and GADD45	Wnt/β-catenin [177] PI3K/ERK/MAPK [178]
(G) Fisetin	Flavonoid (Figure 2G)	Apples, Onions, Kiwi, Cucumber	Ischemic stroke neuroprotective [179] anticancer	MDA-MB-231, MDA-MB-468, MDA-MB-157, SKBR3, MCF-7	xenograft	Bid, Bad, Bak, Bax Aurora B kinase	MAPK/ERK1/2 [180] PI3K/Akt/mTOR NF-κB
(H) Resveratrol	Phytoalexin (Figure 2H)	Red grapes, Blueberries Raspberries	Hyperlipidemia diabetes, atherosclerosis	MDA-MB-435, MDA-MB-231	MDA-MB-231 xenograft	GF-1, MMP2, S6 ribosomal protein, MED28, VEGF	EGFR/PI3K/Akt MAPK [181,182]
(I) Curcumin	Phytopolyl-phenol (Figure 2I)	Turmeric	Food additive, cosmetics, Neuro-degenerative diseases, arthritis	MDA-MB-231, MDA-MB-468, SUM149 PT, SUM159PT	MDA-MB-231 xenograft	VEGFR2/3, EGFR [183,184], Rac1, NF-kB, Akt [185], p53	NF-κB [25] EMT
(J) Maximiscin	Polyketide-shikimate-NRPS-hybrid metabolite (Figure 2J)	Tolypocladium sp in co-culture with bacteria	Data not available	MDA-MB-468	MDA-MB-468 xenograft-	p53, Chk-1 and Chk-2 [186]	DNA damage response
(K) Cyclopamine	Steroidal jerveratrum alkaloid (Figure 2K)	Corn lily	Hypertension, Cardiac diseases, Psoriasis, Basal cell carcinoma, Teratogenic	MDA-MB-231 (is resistant to cyclopamine due low Smo expression) [187], MDA-MB-435	Mouse 4T1	SMO, GLI1 cyclin D1, NF-κB, MMP2 and MMP9 [188]	Hedgehog [189] MAPK/ERK [188]
(L) Capsaicin	Alkaloid (Figure 2L)	Chilli pepper	Pain	MDA-MB-231, BT-474, SKBR3	MDA-MB-231 xenograft	c-Src, FAK and Paxillin MMP2 and MMP9 [190] cyclin D1	EGFR/HER-2 [191]
(M) Genistein	Isoflavanoid (Figure 2M)	Soybeans	Helminthic infection, osteoporosis, cardiovascular diseases, menopause cancer [192]	MDA-MB-231, MDA-MB-468, T47D, MCF-7	MDA-MB-231 xenograft	MMP-9 p21 VEGF TGF-β [193] Bcl-2, Bax, p53 [194]	Hedgehog [195] PTEN/PI3K/Akt (inhibition of mammosphere formation) [196] EGFR [197]
Natural Compound: Having Pro-Carcinogenic Effect in TNBC
(N) Asparagine	Non-essential amino acid (Figure 2N)	Asparagus Potatoes, Legumes, Beef, Egg, Fish	Biosynthetic role	4T1, MDA-MB-231	MDA-MB-231 Mouse 4T1 xenograft	Twist E-cadherin [198]	EMT [198]