Table 1.

Anti-BCSCs effects of food-derived polyphenols.

Compound	Polyphenol concentration	Effects on CSCs	Molecular targets	References
	15 μM	inhibit migration, invasion and EMT	a↑E-cadherin/β-catenin complex; ↓nuclear β-catenin; b↑epithelial markers (E-cadherin, cytokeratin-18 and -19); ↓β-catenin transcriptional targets (cyclin D1, c-Myc, and Slug); ↓EMT-promoting factors (vimentin, MMP-2 and MMP-9)	(Mukherjee et al., 2014)
	10–40 μM 100 mg/kg/d	inhibit mammosphere formation; induce autophagy; inhibit tumor growth in vivo; inhibit ALDH + BCSCs tumorigenicity in vivo	↓β-catenin and cyclin D1 ↑LC3-II, Beclin1 and Atg7	(Fu et al. 2014)
	50 μM 25 mg/kg/d	reduce invasive ability inhibit tumor growth	↑miR-16, -141, -143, and -200c ↑Argonaute2 (Ago2) ↓Zeb1 ↑E-cadherin	(Hagiwara et al. 2012)
	50-100 μM 22.4 kg/body weight	reduce mammosphere formation; reduce breast cancer cells viability; induce BCSCs apoptosis; inhibit tumor growth in vivo suppress lipid syntheses	↓fatty acid synthase ↑pro-apoptotic genes (DAPK2, BNIP3)	(Pandey et al. 2011)
	50-100 μM	decrease BCSCs proliferation; induce BCSCs apoptosis; down-regulate lipogenesis; inhibit mammosphere formation;	↓SREBP1 ↑pro-apoptotic genes (DAPK2, BNIP3) ↓SREBP1 downstream genes (ACLY, ACC1 and FAS)	(Pandey et al. 2013)
	25,50 μM	attenuate migrational and invasive ability decrease proportion of BCSCs inhibit mammosphere formation	↓Cyclin D1and c-Myc ↓MMP-2 and -9 ↓Sox-2 and CD44 ↓p-Akt and p-Stat3	(Suh, Kim, and Surh 2018)
Resveratrol analog HS-1793	0.6–2.5 μM 1.5 mg/kg	reduce invasive ability enhance radiosensitivity and apoptosis induced by radiotherapy	↓Oct4, KLF4 and Sox2 protein ↓VEGF ↓HIF-1α	(Choi et al. 2016)
	12.5–50 μM	inhibit size and number of mammo-spheres; decrease population of ALDH + cells; suppress EMT and migration;	↓Hsp27 ↓N-cadherin and twist ↑E-cadherin	(Li et al. 2011)
	12.5-50 μM	repress BCSCs inhibit tumor growth inhibit VM capability	↓Hsp27	(Lee et al. 2014)
	20 μM	inhibition migration and population of ALDH + cells	↓Hsp27	(Lee et al. 2012)
	0.7 μM	decrease population of CD44+/CD24− cells improve chemosensitivity	↓nuclear Y-box binding protein 1 ↓P-glycoprotein	(Li, Zhao, Wang, Yuan, et al. 2018)
	50 μM	decrease population of CD44+/CD24− cells inhibit mammosphere formation inhibit tumor growth	↓PI3K/Akt/mTOR	(Li, Zhou, Wang, Liu, et al. 2018)
	10-40 μM	inhibit mammosphere formation; inhibit CD44+/CD24− cells	↓ER-α36 ↓EGFR	(Pan et al. 2016)
	20–160 μg/mL 16.5 mg/kg	induce apoptosis of the ALDH + SUM-149 cells; inhibit mammosphere formation; inhibit tumor growth in xenograft mouse model	↓lymphangiogenesis-promoting genes ↓VEGF-D	(Mineva et al. 2013)
EGCG analogs	10,20 μM	inhibit mammosphere formation; inhibition CD44+ high/CD24− low cells		(Chen et al. 2012)
	0-30 μM 0–50 mg/kg	inhibit mammosphere formation; decrease ALDH + levels in xenograft tumors; decrease CD44+CD24− population;	↓Smo ↓Gli1	(Fan et al. 2013)
	2 μM, and 40 nM	induce differentiation of BCSCs; decrease CD44+/CD24−/ESA+ cells;	↑differentiated cell markers (E-cadherin, α-smooth muscle actin and Claudin-1 genes) ↓stem cell markers (Fibronectin and Snail); ↑ phospho-Akt308/473 ↑ phospho-ERK1/2 ↑Amphiregulin ↑phospho-β-catenin	(Liu et al. 2016)
	2 μM, and 40 nM	inhibit adipogenesis inhibit mammosphere formation;	↑mammary tumor suppressor (PTEN and E-cadherin) ↓Pparγ ↓fatty acid synthase ↑estrogen receptor b	(Montales et al. 2013)
	2 μM, and 40 nM 1–40 μM	inhibit mammosphere formation inhibit primary and secondary mammo-sphere formation; decrease CD44+/CD24− cells proportion;	↑PTEN ↓Cleaved Notch1 ↓Hes1 and Cyclin D1	(Montales et al. 2012) (Ray, Vasudevan, and Sengupta 2015)
	5-25 μM	inhibit mammosphere formation; decrease CD44 expression of BCSCs; increase chemosensitivity of BCSCs; induce cell necrosis phenomena;	↓hedgehog ↑p-β-catenin ↓CD44 ↓c-Myc ↓cyclin D1	(Wu, Hong, et al. 2015)
	–	inhibit metastasis; inhibit tumor growth; inhibit mammosphere formation; suppress cell migration and mobility	↓PI3K/AKT signaling ↓MAPK/ERK signaling ↓STAT3 signaling	(Vuong et al. 2016)
	10 μM 20 mg/kg Body Weight	decrease mesenchymal features; inhibit mammosphere formation; inhibit tumor growth;	↓TGFβ-SMADs Signal ↑miR-148a ↓DNMT1 and DNMT3a	(Jiang et al. 2016)
	25, 50 μM 50 mg/kg/d	inhibit self-renewal and multi-differentiation; reduce BCSCs proportion; inhibit tumor growth;	↓heat shock 70kDa protein 5 ↓β-catenin/ABCG2 signaling	(Wang Wang, et al. 2014)
	25, 50 μM 50 mg/kg/d	block self-renewal BCSCs; reduce BCSCs population; induce BCSCs G0/G1 phase arrest; inhibit tumor growth;	↓DNMT1 methyltransferase ↑WIF1 ↓β-catenin signaling	(Wang Wang, et al. 2015)
Curcumin + piperine	5,10 μM	inhibit mammosphere formation; reduce the percent of cells bearing ALDH1+	↓Wnt signaling	(Kakarala et al. 2010)
Curcumin + Mitomycin C	5–40 μM 100 mg/kg	nhibit mammosphere formation; reduce cells expressing CD44+CD24−/low; inhibit tumor growth in vivo	↓ABCG2 and ABCC1	(Zhou et al. 2015)
Curcumin + EGCG	10 μM, 10 μM	inhibit mammosphere formation; inhibit invasion; reduce CD44−expressing subpopulation	↓p-STAT3 ↓nuclear STAT3-NFkB	(Chung Seyung 2015)

^a↓Represents down-regulation;

^b↑Represents down-regulation.

Abbreviations: ACC1, acetyl CoA carboxylase 1; ALDH, aldehyde dehydrogenase; ACLY, ATP-citrate lyase; BCSCs, breast cancer stem cells; EMT, epithelial mesenchymal transition; EGFR, epidermal growth factor receptor; ER-α36, estrogen receptor-α36; FAS, fatty acid synthase; GSK3β, glycogen synthase kinase 3β; Hsp, Heat shock protein; MMP, metal matrix proteinase; PPARγ, Peroxisome proliferator-activated receptor γ; SREBP1, sterol regulatory element binding proteins1; VEGF, vascular endothelial growth factor.