Molecular Mechanisms of Biologically Active Compounds from Propolis in Breast Cancer: State of the Art and Future Directions

ABSTRACT

Breast cancer is the most commonly diagnosed oncological malignancy in women. The search for better treatment alternatives has placed attention on natural products. Propolis, a resinous bee product rich in polyphenols, has important anti-proliferative properties. This review describes the molecular mechanisms of propolis and several of its constituents in breast cancer, with a special focus on those involved in their anti-proliferative, pro-apoptotic and anti-metastatic activities. Their therapeutic potential in breast cancer is discussed, both individually, and in combination, identifying opportunities for future research. Synergistic effects of propolis-derived chemicals could lay the foundation for future breakthroughs in breast cancer treatment strategies.

KEYWORDS:

• Breast cancer
• propolis
• polyphenols
• molecular mechanisms
• therapy

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Abbreviations

26S:26S proteasome

(3)H-DG: (3)H deoxyglucose

4EBP: eIF4E-binding protein

γ-H2AX: H2A histone family member X

Δψ_m: mitochondrial membrane potential

ACC: acetyl Co-A carboxylase

AEG-1: astrocyte elevated gene-1

Akt: protein kinase B

ALDH1A1: aldehyde dehydrogenase 1 family, member A1

AMPK: AMP-activated protein kinase

AP-1: activator protein 1

AR: androgen receptor

ATF4: activating transcription factor 4

ATM: protein kinase ataxia-telangiectasia mutated

AVO: acidic vesicular organelle

Bad: Bcl associated agonist of cell death

Bax: Bcl-2 associated X protein

Bcl-2: B-cell lymphoma 2

Bcl-xL: B-cell lymphoma-extra large

Bid: BH3 interacting domain death agonist

BRCA1: breast cancer type 1 susceptibility protein

Ca: calcium

CAPE: caffeic acid phenethyl ester

CASP8: caspase 8 encoding gene

CBP: cuban brown propolis

CCND2: cyclin D2 encoding gene

Cdc2: cell division cycle protein 2

CDC25C: M-phase inducer phosphatase 3

CDC34: ubiquitin-conjugating enzyme encoding gene

CDK: cyclin-dependent kinase

CDK5RAP1: CDK5 regulatory subunit associated protein 1 encoding gene

CHOP: CCAAT-enhancer-binding protein homologous protein

c-Myc: cellular myelocytomatosis oncogene

Cox2: prostaglandin-endoperoxide synthase 2 encoding gene

CTGF: connective tissue growth factor

Cx43: connexin 43

CXCR4: C-X-C chemokine receptor type 4

CYP19: aromatase cytochrome P450

CYP1A1: cytochrome P450 1A

CYR61: cysteine-rich angiogenic inducer 61

DFF-45: DNA fragmentation factor 45

DR: death receptor

E2: 17-β-estradiol

EGFR: epidermal growth factor receptor

Egr-1: early growth response protein 1

eIF2a: eukaryotic translation initiation factor 2A

ELK1: ETS like-1 protein

EMT: epithelial-to-mesenchymal transition

ER: estrogen receptor

ERα: estrogen receptor alpha

ERβ: estrogen receptor beta

ERK: extracellular signal-regulated kinase

FADD: Fas-associated protein with death domain

Fas: FS7-associated cell surface antigen

FasL: Fas ligand

FOXO3: Forkhead box O3

GADD45α: growth arrest and DNA damage inducible alpha

gBRCA1: germline BRCA1

GLUT1: glucose transporter 1

GM-CSF: granulocyte-macrophage colony-stimulating factor

GRP78: glucose regulated protein 78

GSK-3: glycogen synthase kinase-3

GSTP1-1: glutathione S-transferase P1-1

H2A.X: histone family member X

HDAC: histone deacetylase

HER2: human epidermal growth factor receptor 2

Hes-1: Hes family BHLH transcription factor 1

HO-1: heme oxygenase-1

HIF-1α: hypoxia-inducible factor 1 alpha

HSF: heat shock factor

HSP: heat shock protein

hTERT: human telomerase reverse transcriptase

IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha

IC₅₀: half maximal inhibitory concentration

IL: interleukin

IQGAP3: IQ motif containing GTPase activating protein 3

IRS-1: insulin receptor substrate 1

JAK: janus kinase

JNK: c-Jun N-terminal kinase

Ki-67: proliferation marker protein

LC3-II: microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate

LDHA: lactate dehydrogenase A

MAPK: mitogen-activated protein kinase

mdr-1: multi-drug resistance-1

MEK: mitogen-activated protein kinase kinase

MMP: matrix metalloproteinase

mTOR: mammalian target of rapamycin

MTT: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide

MUC1: mucin 1

NF-κB: nuclear factor kappaB

NQO1: NAD(P)H quinone dehydrogenase 1

OPCML: opioid binding protein/cell adhesion molecule like

OS: overall survival rate

p19: RNA silencing suppressor p19

p21: cyclin-dependent kinase inhibitor

p27: cyclin-dependent kinase inhibitor

p38: mitogen-activated protein kinase

p62: sequestosome 1

P4501B1: cytochrome CYP1B1 gene

p53: cellular tumor antigen p53

p57: cyclin-dependent kinase inhibitor 1C

p65: nuclear factor NF-kappaB p65 subunit

p70S6K: p70-S6 kinase

PARP: poly adenosine diphosphate ribose polymerase

PCNA: proliferating cell nuclear antigen

PgR: progesterone receptor

PI3K: phosphatidilynositol-4,5-biphosphate 3-kinase

PI3KCA: phosphatidilynositol-4,5-biphosphate 3-kinase catalytic subunit alpha

PKCδ: protein kinas C-delta

PKM2: pyruvate kinase muscle isozyme 2

PLK-1: polo-like kinase 1

PPARα: peroxisome proliferator-activated receptor alpha

PR: progesterone receptor

PTEN: phosphatase and tensin homolog

Rac1: Ras-related C3 botulinum toxin substrate 1

Raf: serine/threonine protein kinase

RAR: retinoic acid receptor

Ras: small GTPase

Rb: retinoblastoma protein

RB1: retinoblastoma protein

RhoA: Ras homolog family member A

ROS: reactive oxygen species

SIRT6: sirtulin 6

Sp1: transcription factor Sp1

STAT: signal transducer and activator o transcription

tap: transporter associated with antigen processing

TAZ: tafazzin

tBid: truncated BH3 interacting domain death agonist

TGF-β: transforming growth factor beta

TNBC: triple negative breast cancer

TNF-α: tumor necrosis factor alpha

UGDH: UDP-glucose 6-dehydrogenase

v-abl: Abelson murine leukemia viral oncogene homolog 1

VEGF: vascular endothelial growth factor

VEGFA: vascular endothelial growth factor A

VGSC: voltage-gated sodium channel

WNT: wingless-related integration site

WST-1: water-soluble tetrazolium salt

YAP: yes-associated protein

Zeb1: Zinc finger E-box binding homeobox 1

Additional information

Funding

This work was supported by the CONACYT (Consejo Nacional de Ciencia y Tecnologia).