Table 3.

Overview of the effects of extra-virgin olive oil minor compounds on breast carcinogenesis and associated molecular and cellular mechanisms. Mechanisms induced in combination with chemotherapeutics are not shown.

Component	Model	Carcinogenesis	Molecular/Cellular Mechanisms	Ref.
Triterpenes
Uvaol	MCF-7	Anti-proliferative	↓ ROS, ↓ H2O2-induced DNA damage	[209]
	MCF-10A, MDA-MB-231	Decrease in proliferation and survival	↓ ROS, ↓ basal DNA damage (at low doses), ↑ H2O2-induced DNA damage	[210]
Erythrodiol	MCF-7	Anti-proliferative, pro-apoptotic	↑ ROS	[209]
	MCF-10A, MDA-MB-231	Decrease in proliferation and survival	↓ ROS, ↑ DNA damage; cycle arrest and apoptosis in MCF-10A	[210]
Maslinic acid	MCF-7		↓ ROS, ↓ H2O2-induced DNA damage	[209]
	MCF-10A, MCF-7, MDA-MB-23	Decrease in proliferation and survival	↓ basal ROS in MCF-10A; ↑ basal ROS in MCF-7 ↑ H2O2-induced DNA damage	[211]
Oleanolic acid	MCF-7	Anti-proliferative, pro-apoptotic	↓ ROS, ↓ H2O2-induced DNA damage	[209]
	MCF-10A, MCF-7, MDA-MB-23	Decrease in proliferation and survival	↑ ROS and H2O2-induced DNA damage in MDA-MB-231 ↓ ROS and H2O2-induced DNA damage in MCF-10A	[211]
	MCF-7, T47D, SKBR3	Growth inhibition, pro-apoptotic	ERα/Sp1-mediated activation of the p53 gene	[212]
	MCF-7, MDA-MB-231		↓ mTOR-Complex 1 and -Complex2 activity (↓mTOR/FRAP1, RICTOR, RAPTOR, AKT, 4E-BP, p70S6k)	[213]
	MCF-7	Anti-proliferative, pro-apoptotic	Transcriptomic changes; modulation of p53-, TNF- and mTOR-signaling pathways genes ↓THBS1, EDN1, CACNG4, CCN2, AXIN2, BMP4 ↑ATF4, SERPINE1, SESN2, PPARGC1A, EGR1 and JAG1	[214]
Phenolic acids
Caffeic acid	MCF-7	Decreased viability	↓ p53, ↑ Mcl-1, ↓ p21 (short treatment), ↑ p21 (long treatment)	[206]
	MCF-7, MDA-MB-231	Anti-proliferative, cycle arrest, pro-apoptotic	↓ IGFIR, ↓ AKT activation; ↓ ER, ↓ Cyclin D1 in MCF-7 cells	[207]
	MCF-7, MDA-MB-231		↓ RAR-β methylation	[208]
Elenolic acid	SKBR3, MCF-7/HER2	Anti-proliferative	↓ HER2	[121]
Gallic acid	MCF-7	Decreased viability	↑ p53, ↑ Mcl-1, ↓ p21 (short treatment), ↑ p21 (long treatment)	[206]
Phenolic alcohols
Tyrosol	SKBR3, MCF-7/HER2	Anti-proliferative	↓ HER2	[121]
Hydroxyty-rosol	In vivo (DMBA)	Growth inhibition, anti- proliferative	Transcriptomic changes in tumors; modulation of apoptosis, cell cycle, proliferation, differentiation, survival and transformation pathways genes; ↑ sfrp4	[115]
			Plasma: ↑ antioxidant capacity, ↓ DNA and protein damage	[116]
	MCF-7	Decreased cell viability, anti-proliferative, blocked G(1)-to-S transition, pro-apoptotic	↓ Pin1, ↓ Cyclin D1	[117,118]
	MCF-7	Anti-proliferative	↓ ERK1/2	[119]
	SKBR3, MCF-7/HER2	Anti-proliferative, pro-apoptotic	↓ FAS, ↓ HER2	[120,121]
	cocultures MCF-7- fibroblast	Inhibition of fibroblast-stimulated MCF-7 proliferation	↓ CCL5 expression in aging fibroblasts	[122]
	SKBR3	Pro-apoptotic	↑ GPER, ↑ ERK1/2, ↑ Bax, ↓ Bcl-2, ↑ Casp-9, ↑ Casp-3, ↓ PARP-1, ↑ p21, ↑ p53, ↓ Cyclin D1	[123]
	MDA and MCF-7	Anti-proliferative, pro-apoptotic	Extracellular production of hydrogen peroxide	[125]
	MCF-10A, MDA-MB-231, MCF-7		Prevents oxidative DNA damage ↓ intracellular ROS level in MCF-10A	[128]
	MCF-10A, MDA-MB-231		Pro-oxidant under specific growth conditions	[126]
	MCF-7		Antioxidant; ↑ Nrf2, ↑ GSTA2, ↑ HO-1	[129]
	MCF-7 under hypoxic conditions		↓ PI3K/AKT/mTOR pathway, ↓ HIF-1α, ↓ PARP-1 At high doses ↑ VEGF, ↑ AM, ↑ Glut1	[130]
	MDA-MB-231, BT549, Hs578T	Inhibition of EMT, migration and metastatic potential	↓ SMAD2/3-dependent TGFβ signaling, ↓ p-LRP6, ↓ LRP6, ↓ β-catenin, ↓ cyclin D1 ↓ SLUG, ↓ ZEB1, ↓ SNAIL, ↓ Vimentin; ↑ ZO-1	[131]
	MCF-7 and T47D	Inhibition of migration and invasion	Induction of autophagy	[133]
	MDA-MB-231	Inhibition of migration and invasion	Induction of autophagy; ↑ LC3-II/LC3-I, ↑ Beclin-1, ↓ p63	[132]
Secoiridoids
Ligstroside	SKBR3, MCF-7/HER2	Anti-proliferative, pro-apoptotic	↓ FAS, ↓ HER2	[120,121]
Oleuropein	In vivo (cancer- stem-cell-enriched orthotopic model)	Treatment with decarboxymethyl oleuropein reduced carcinogenesis	↓ DNMT, ↓ mTOR	[138]
	MCF-7	Decreased cell viability, inhibited cell proliferation, blocked G(1)-to-S transition, pro-apoptotic		[117]
	MDA-MB-468, MDA-MB-231	Growth inhibition, S-phase cell-cycle arrest-mediated apoptosis	Transcriptomic changes in apoptosis-involved genes (Casp1, Casp14, FADD, TNFRSF21, GADD45A, CYCS and BNIP2)	[135]
	MCF-7, MDA-MB-231	Pro-apoptotic	Increased the expression of pro-apoptotic genes and tumor-suppressor miRNAs; decreased the expression of anti-apoptotic genes and oncomiR	[136]
	MCF-7	Anti-proliferative, pro-apoptotic, inhibition of migration	↓ mir-21, ↓ mir-155	[137]
	MCF-7	Reduced viability and invasiveness, pro-apoptotic	↓ HDAC2, ↓ HDAC3, ↓ HDAC4	[139,140]
	MCF-7	Anti-proliferative	↓ ERK1/2	[119]
	MCF-7	Reduced viability, cell- cycle arrest	↓ PTP1B	[141]
	MCF-7	Pro-apoptotic	↑ p53, ↑ Bax, ↓ Bcl-2	[142]
	MDA-MB-231	Anti-proliferative, pro-apoptotic, cell-cycle arrest	↑ Bax, ↑ Casp3, ↓ Bcl2, ↓ Survivin; ↓ NF-kB, ↓ CycD1, ↑ p21	[143]
	MDA-MB-231	Pro-apoptotic	↑ ROS, ↓ NF-kB	[144]
	MDA-MB-231	Cell growth inhibition	↓ PAI-1, ↑ Casp8	[145]
	SKBR3, MCF-7/HER2		↓ FAS	[120]
	SKBR3, MCF-7/HER2, MCF-10A/HER2	Anti-proliferative, pro-apoptotic	↓ HER2	[121,146]
	SKBR3	Pro-apoptotic	↑ GPER, ↑ Bax, ↓ Bcl-2; ↑ Casp-9, ↑ Casp-3, ↓ PARP-1; ↑ p21, ↑ p53, ↓ Cyclin D1	[123]
	MCF-10A, MDA-MB-231		Pro-oxidant under specific growth conditions	[126]
	MDA-MB-231	Anti-proliferative, pro-apoptotic	Pro-oxidant activity, ↓ SOD2 ↓ catalase, ↑ intracellular and mitochondrial ROS ↓ CycB2, ↓ CycD1, ↑ Casp9, ↓ PARP-1	[148]
	MCF-7 and T47D	Inhibition of migration and invasion	Induction of autophagy	[133]
	MDA-MB-231	Inhibition of migration and invasion	Induction of autophagy; ↑ LC3-II/LC3-I, ↑ Beclin-1, ↓ p62	[132]
	MCF-7	Inhibition of migration	↓ Sirt1, ↑ ECad, ↓ ZEB1, ↓ MMP-2, ↓ MMP-9, ↑ p53	[150]
	MDA-MB-231	Decreased viability and migration	↓ miR-194-5p, ↓ PD-L1, ↑ XIST	[151]
	MDA-MB-231		↓ glycolysis rate	[152]
Oleocanthal	In vivo (MMTV-PyVT; patient-derived xenograft)	Suppressed initiation and incidence	Transcriptomic changes, ↓ Myc	[155]
	In vivo (MDA- MB-231 xenograft)	Inhibition of tumor proliferation and growth	↓ c-Met, ↓ Ki-67, ↓ CD31	[156]
	In vivo (BT-474 and MDA-MB-231 xenografts)	Prevention of locoregional recurrence, tumor growth inhibition	↓ c-Met, ↓ HER2; ↑ ECad, ↓ Vimentin; ↓ CA 15-3 in serum	[157]
	In vivo (BT-474 xenograft)	Tumor growth inhibition	↓ ERα	[158]
	MCF-7, BT-474, MDA-MB-231	Inhibition of proliferation and survival	↓ Met, ↓ AKT, ↓ ERK; ↓ CycD1, ↓ Cdk6, ↑ p21, ↑ p27; ↓ Brk/Paxillin/Rac1; ↑ ECad, ↑ ZO-1, ↓ Vimentin, ↓ β-catenin; ↑ Casp8, ↑ Casp3, ↓ RIP, ↓ PARP-1	[156]
	MCF-7, MDA-MB-231	Anti-proliferative, inhibition of migration and invasion	↓ c-Met activation. ↓ microvessel density marker (CD31)	[154]
	MCF-7, T47D, MDA-MB-231	Anti-proliferative	↓ mTOR and inducing apoptosis in MDA-MB-231 cells	[159]
	MCF-7, BT-474, T47D	Inhibition of estrogen- induced proliferation	↓ ERα in BT-474	[158]
	MCF-7, MDA-MB-231	Anti-proliferative, inhibition of migration	Modulation of Ca2+ entry through TRPC6	[160]
Lignans
Pinoresinol	SKBR3, MCF-7/HER2		↓ FAS	[120]
	SKBR3, MCF-7/HER2, MCF-10A/HER2	Anti-proliferative, pro-apoptotic	↓ HER2	[121,202]
	MCF-7 and TD47D	Cytotoxicity		[203]
	MDA-MB-231	Anti-proliferation	↑ p21	[204]
	MDA-MB-231, MCF-7, MCF-10A	Cytotoxic, anti-proliferative and pro-oxidant	↓ ROS, ↓ DNA damage in MCF-10A cells; ↑ ROS in cancer cells after H2O2 treatment	[205]
Acetoxypinoresinol	SKBR3, MCF-7/HER2		↓ FAS	[120]
	SKBR3, MCF-7/HER2, MCF-10A/HER2	Anti-proliferative, pro-apoptotic	↓ HER2	[121,202]
Flavonoids
Apigenin	In vivo (BT-474 xenograft model)	Tumor growth inhibition, anti-proliferative, pro- apoptotic	↓ Ki-67, ↓ HER2, ↓ VEGF, ↑ RANKL	[161]
	In vivo (MDA- MB-231 xenograft)	Tumor growth inhibition, pro-apoptotic	↑ ubiquitinated proteins, ↑ Bax, ↑ IκBα	[162]
	Hs578T, MDA- MB-231, MCF-7	Anti-proliferative, cell- cycle arrest, pro-apoptotic	↓ PI3K, ↓ PKB, ↑ FOXO3a, ↑ p21, ↑ p27; ↑ p53; ↑ PARP-1; ↑ Cyt C	[170]
	SKBR3, MCF-7/HER2		↓ FAS	[120]
	MDA-MB-231	Anti-proliferative, pro-apoptotic	↑ Casp-3, ↑ proteosome activity, ↑ ubiquitinated proteins, ↑ Bax, ↑ IκBα, ↑ PARP-1	[162]
	MCF-7, MDA-MB-468	Growth inhibition, cycle arrest	↓ cyclin B1, ↓ cyclin D1, ↓ cyclin A, ↓ CDK1, ↓ CDK4, ↓ Rb (in MCF-7), ↓ ERK (in MDA-MB-468)	[163]
	T47D, MDA-MB-231	Anti-proliferative, pro-apoptotic	↑ Casp3, ↓ PARP-1, ↑ Bax ↓ Bcl-2; ↑ LC3-II	[156]
	MDA-MB-231 spheroids—lymph endothelial cells		↓ MMP-1, ↓ CYP1A1 in MDA-MB-231 cells ↓ FAK in lymph endothelial cells	[185]
	MDA-MB-468, SKBR3, mouse 4T1 cells		↓ PD-L1, ↓ STAT1 activation, ↑ T-cell proliferation in co-culture	[188]
	MDA-MB-231	Decreased viability	↓ CCL2, ↓ GMCSF, ↓ IL-1α, ↓ IL-6, ↓ IKBK-e	[189]
	human breast tumor phage display cDNA librar; MDA-MB-231		160 direct targets, hnRNPA2 top candidate ↓ hnRNPA2 activation, modulation of splicing in MDA-MB-231 cells	[190]
	MCF-7, MDA MB-231	Decreased viability, pro-apoptotic	↑ lipid peroxidation, ↑ DNA damage	[193]
Luteolin	In vivo (MDA-MB-231 xenograft)	Reduced tumor burden Reduced tumor growth	↓ Ki-67	[164,180]
	In vivo (mouse mammary tumor cells)	Tumor growth inhibition, pro-apoptotic, angiogene- sis inhibition	↑ p53, ↑ Bax, ↓ Bcl-2	[174]
	In vivo (DMBA- induced)	Tumor growth inhibition	Antioxidant, ↑ SOD, ↑ CAT, ↑ GPx	[192]
	In vivo (DMBA- induced)	Tumor growth inhibition, anti-angiogenic	↓ VEGF, ↓ CD31	[187]
	In vivo (T47D xenograft)	Tumor growth inhibition, anti-angiogenic	↓ VEGF, ↓ CD31	[186]
	In vivo (MDA-MB-435, MDA-MB-231(4175)LM2 xenograft)	Inhibition of lung metastases		[177]
	In vivo (MDA-MB-231 xenograft)	Inhibition of lung metastases	↓ Slug, ↓ Vimentin	[178]
	In vivo (4T1 implantation)	Tumor growth inhibition	↓ YAP, ↓ TAZ	[183]
	In vivo (MCF-7, 4T1 implantation)		↑ SOD, CAT in serum ↓ SOD, ↓ CAT in tumor	[191]
	MDA-MB-231	Cell growth inhibition, cell-cycle arrest, pro-apoptotic	↑ p21, ↓ PLK1, ↓CycB1, ↓ CycA, ↓ CDK1, ↓ CDK2; ↑ Bax; ↓ EGFR, ↓ AKT, ↓ ERK1/2, ↓ p38	[164]
	MCF-7	Anti-proliferative, cell- cycle arrest, pro-apoptotic	↓ EGFR, ↓ AKT, ↓ ERK1/2, ↓ Stat3	[165]
			↓ IGFR1, ↓ AKT, ↓ ERα	[166]
	MCF-7	Anti-proliferative	Regulation of gene expression (estrogen receptor pathway and cell cycle genes)	[167]
	Hs578T, MDA- MB-231, MCF-7	Anti-proliferative, cell- cycle arrest, pro-apoptotic	↓ PI3K, ↓ PKB, ↑ FOXO3a, ↑ p21, ↑ p27; ↑ p53; ↑ PARP-1; ↑ Cyt C	[170]
	MDA-MB-231	Anti-proliferative, pro-apoptotic	↓ FAS	[171]
	SKBR3, MCF-7/HER2		↓ FAS	[120]
	MDA-MB-231	Anti-proliferative, cell- cycle arrest, pro-apoptotic	↓ NF-kB, ↓ Myc, ↓TERT	[172]
	MCF-7	Anti-proliferative, cell- cycle arrest, pro-apoptotic	↑ DR5, ↑ Casp8, ↑ Bax, ↓ Bcl-2, ↑ Casp9, ↑ Casp3	[173]
	MCF-7, MDA- MB-231, SKBR3	Decreased viability, pro-apoptotic	↑ ERK/p38 activation, AIF translocation	[176]
	MDA-MB-435, MDA-MB-231(4175)LM2	Anti-proliferative, pro-apoptotic, reduced migration	↓ VEGF secretion	[177]
	MDA-MB-231, BT5-4	Inhibition of migration and invasion	↓ β-catenin, ↓ N-cadherin, ↓Vimentin, ↑ E-cadherin,	[178]
			↑ Claudin
	SUM-149	Reduced enrichment in stem cells and growth, pro-apoptotic	↓ RSK, ↓ YB-1, ↓ Notch4	[179]
	MCF-7, MDA-MB-231	Anti-proliferative, cycle arrest, decreased migration	↓ Notch1, ↓ Hes1, ↓ Hey1, ↓ Hey2, ↓ VEGF, ↓ MMP-2, ↓ MMP-9 ↑ miR-34a, ↑ miR-181a, ↑ miR-139-5p, ↑ miR-224, ↑ miR-246, ↓ miR-155	[180]
	BT-20	Anti-proliferative, reduced migration and invasion	↓ AKT, ↓ mTOR, ↓ MMP-9, ↓ H3K27ac, ↓ H3K56ac	[181]
	MDA-MB-231	Reduced viability, cycle arrest, pro-apoptotic	↓ CXCR4, ↓ MMP-2, ↓ MMP-9	[182]
	MDA-MB-231, 4T1	Reduced viability, inhibition of colony formation	↓ YAP, ↓ TAZ, ↓ N-Cad, ↓ Vimentin, ↓ FN1, ↑ E-Cad	[183]
	MDA-MB-231 spheroids—lymph endothelial cells		↓ MMP-1, ↓ CYP1A1 in MDA-MB-231 cells ↓ FAK, ↓ Ca2+ release in lymph endothelial cells	[185]
	T47D, BT-474	Reduced viability, pro-apoptotic	↓ VEGF	[186]
		Reduced mammosphere formation in T47D cells
	MDA-MB-468		↓ PD-L1	[188]
	MCF-7, 4T1		↓ glycolytic flux (under hypoxia)	[191]

↓: decrease, downmodulation or inactivation; ↑: increase, upmodulation or activation.