Molecular Links between Central Obesity and Breast Cancer
Abstract
:1. Introduction
2. Tumor Microenvironment vs. Adipose Tissue Microenvironment and Their Role in Tumor-Promoting Low-Grade Inflammation
3. The Hormones, Their Signaling Pathways, Central Adiposity, and Breast Cancer
3.1. Leptin
3.2. Adiponectin
3.3. Estrogen
4. Exosomes, MicroRNAs, and Their Possible Role in the Interplay between Central Adiposity, and BC
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
BC | Breast Cancer |
TNBC | Triple Negative Breast Cancer |
ER | Estrogen Receptor |
PR | Progesteron Receptor |
HER2 | Human Epidermal Growth Factor Receptor 2 |
WAT | White Adipose Tissue |
BMI | Body Mass Index |
PR+ | Progesterone Receptor Positive |
VAT | Visceral Adipose Tissue |
TAMS | Tumor Associated Macrophages |
Tregs | Regulatory T Cells |
Th2 | Type 2 T Helper Cells |
Bregs | Regulatory B Cells |
CAF | Cancer Associated Fibroblasts |
M1 | Type 1 Macrophages |
M2 | Type 2 Macrophages |
NK | Natural Killer Cells |
INF γ | Interferon Gamma |
TNFα | Tumor Necrosis Factor Alpha |
IL | Interleukin |
ROS | Reactive Oxygen Species |
STAT3 | Signal Transducer and Activator of Transcription 3 |
NRF 2 | Nuclear Factor 2 |
AP1 | Activator Protein 1 |
HIF 1α | Hypoxia-Inducible Factor 1 Alpha |
PPAR | Peroxisome Proliferator-Activated Receptor |
MMPs | Matrix Metalloproteinases |
AKT | Protein Kinase B |
NFκβ | Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells |
TLR | Toll-Like Receptor |
PAMPs | Pathogen-Associated Molecular Patterns |
CRP | C Reactive Protein |
LPS | Lipopolysaccharide |
MCP 1 | Monocyte Chemoattractant Protein 1 |
ICAM1 | Intercellular Adhesion Molecule 1 (Cd54) |
MIP | Macrophage Inflammatory Proteins |
VEGF | Vascular Endothelial Growth Factor |
ATC | Subcutaneous Stem Cells |
NLRP3 | Cryopyrin |
KO | Knock-Out |
WT | Wild Type |
COX 2 | Cyclooxygenase 2 |
PGE2 | Prostaglandin E2 |
cAMP | Cyclic Amp |
JNK | Jun N-Terminal Kinase |
E2 | Estradiol |
PI3K | Phosphoinositide 3-Kinase |
BRCA1 | Breast Cancer Type 1 Susceptibility Protein |
KEAP 1 | Kelch-Like ECH-Associated Protein 1 |
ARE | Antioxidant Response Element |
PP | Physagulide P |
EGFR | Epidermal Growth Factor Receptor |
MAPK | Mitogen Activated Protein Kinase |
FGF | Fibroblast Growth Factor |
EPHA 2 | Ephrin Type-A Receptor 2 |
ATM | Adipose Tissue Macrophage |
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Cytokine | Source of Secretion | Immune Significance | Role in BC | Ref. |
---|---|---|---|---|
IL-1β | Myeloid cells, Macrophages, T cells | - stimulates secretion of other pro-inflammatory mediators | - leads to poor prognostic - promotes tumor growth, and metastasis - induces invasiveness in TNBC (triple negative BC) | [54,55,56] |
IL-6 | T cells, Macrophages | - binds to IL6sR (soluble receptor) and stimulates STAT3 activation in cells that express gp130 - enhances inflammation - fights against infections | - leads to poor prognostic - increased levels in advanced breast tumor stages | [57,58] |
IL-8 | Macrophages, Epithelial cells, Smooth muscle cells, Endothelial cells | - has increased levels in inflammation - plays a key role in neutrophil degranulation | - increases metastatic potential of ER-, and ER+ BC cells - highly expressed in ER- BC - induces BC progression by stimulating invasion/metastasis | [59,60] |
IL-17 | Th17 | - leads to inflammatory diseases such as Rheumatoid arthritis. - induces allergic responses - enhances inflammation by recruiting other proinflammatory cytokines | - induces overexpression of VEGF - promotes tumor cells survival - inhibits the antitumor immune response | [61,62] |
IL-18 | Macrophages | - together with IL-12, induces cell mediated immunity | - inhibits BC cell proliferation - induces inflammatory reactions - enhances BC migration - poor prognostic in TNBC | [56,63,64,65] |
TNFα | Macrophages, NK cells, Neutrophils, Mast cells, Eosinophils | - relevant in inflammatory setup in BC cells - key proinflammatory cytokine | - enhances inflammatory process -mediates NFκB signaling pathway - regulates the immune cells - induces fever, and apoptosis - promotes BC migration | [66,67,68] |
Name | Expression in Obese VAT | Expression in BC | Target Gene(s) | Biological Effect in BC | Ref. |
---|---|---|---|---|---|
miR-148b | ↓ | ↓ | Dnmt3b, Itga5, Alcam | proliferation, malignant transformation, pro-apoptosis, radio sensitivity, invasion, migration | [122,123,124,125,126] |
miR-23 | ↑ | ↑ | Par2 | invasion, lung metastasis | [122,133,134,135,136] |
miR-200 | ↑ | ↑ | E-Cadherin EPHA2 | invasion, migration, proliferation | [137,138,139,140] |
miR-141 | ↑ | ↓ | [137,141,142] | ||
miR-429 | ↑ | ↓ | [137,143] | ||
miR-155 | ↑ | ↑ | Smad1/5, Casp3, Fadd, Rip1, Irak, Pka, Apaf-1, Foxo3a, Bcl-2, Socs1, Smad2, Hif, Pu.1,Mcsf, Tp53inp1 | Invasion, apoptosis, proliferation, angiogenesis, differentiation | [144,145,146] |
miR-20b | ↑ | ↑ | Pten* | Cell growth and proliferation | [149,150] |
miR-296 | ↑ | ↓ | hTERT | Shorter telomeres, induce apoptosis | [150,151] |
let-7f | ↑ | ↑ | THBS1 | No effect on apoptosis or proliferation | [150,152] |
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Zimta, A.-A.; Tigu, A.B.; Muntean, M.; Cenariu, D.; Slaby, O.; Berindan-Neagoe, I. Molecular Links between Central Obesity and Breast Cancer. Int. J. Mol. Sci. 2019, 20, 5364. https://doi.org/10.3390/ijms20215364
Zimta A-A, Tigu AB, Muntean M, Cenariu D, Slaby O, Berindan-Neagoe I. Molecular Links between Central Obesity and Breast Cancer. International Journal of Molecular Sciences. 2019; 20(21):5364. https://doi.org/10.3390/ijms20215364
Chicago/Turabian StyleZimta, Alina-Andreea, Adrian Bogdan Tigu, Maximilian Muntean, Diana Cenariu, Ondrej Slaby, and Ioana Berindan-Neagoe. 2019. "Molecular Links between Central Obesity and Breast Cancer" International Journal of Molecular Sciences 20, no. 21: 5364. https://doi.org/10.3390/ijms20215364