Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential
Abstract
:1. Introduction
2. The TNBC Secretome
2.1. Cytokines and Growth Factors
2.2. Extracellular Matrix Proteins
2.3. Proteases and Protease Inhibitors
2.4. Other Proteins
2.4.1. Membrane and Extracellular Vesicle Proteins
2.4.2. Peptide Hormones
2.4.3. Metabolic Proteins
2.5. Drug-Induced Changes
3. Secreted Factors Outside of the Primary Tumor
3.1. Influence of TNBC on Surrounding Cells
3.2. Proteins Secreted from the TME
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
APP | amyloid-β precursor protein |
APLP2 | amyloid-β precursor-like protein 2 |
BBB | blood–brain barrier |
CAF | cancer-associated fibroblasts |
CM | conditioned media |
CTSD | cathepsin D |
CTSZ | cathepsin Z |
ECM | extracellular matrix |
EFEMP1/FBLN3 | fibulin 3 |
EMT | epithelial–mesenchymal transition |
ER | estrogen receptor |
EV | extracellular vesicle |
FBLN1 | fibulin 1 |
FN | fibronectin |
FST | follistatin |
GDF15 | growth differentiation factor 15 |
IGFBP | insulin-like growth factor-binding protein |
IRE1 | inositol-requiring enzyme 1 alpha |
LCN2 | lipocalin 2 |
LDL | low-density lipoprotein |
LEC | lymphatic endothelial cells |
LPA | lipoprotein A |
MEC | microvascular endothelial cells |
MIC-1 | macrophage inhibitory cytokine-1 |
MMP | matrix metalloproteinase |
MSC | mesenchymal stromal cell |
MTA | microtubule-targeting agents |
OGF | opioid growth factor |
PAI1 | plasminogen activator inhibitor 1 |
PENK | proenkephalin |
PLAT | tissue plasminogen activator |
PLG | plasminogen |
PR | progesterone receptor |
SASP | senescence-associated secretory phenotype |
SERPINE1 | serine peptidase inhibitor E1 |
SNPs | single-nucleotide polymorphisms |
STX | sialyl transferase X |
suPAR/PLAUR | soluble form of the urokinase receptor |
TF | tissue factor |
THBS1 | thrombospondin |
TIMP | tissue inhibitor of metalloproteinases |
TIS | therapeutic-induced senescent |
TME | tumor microenvironment |
TNBC | triple-negative breast cancer |
TSPAN11 | tetraspanin 11 |
uPA/PLAU | urokinase plasminogen activator |
uPAR | urokinase plasminogen activator receptor |
VEGF | vascular endothelial growth factor |
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Cytokines | ||||
---|---|---|---|---|
Protein | Aliases | Source | Evidence | Refs. |
CCL2 | Chemokine (C-C motif) ligand 2 | Adipose-derived MSCs | ADMSCs treated with TNBC CM | [6] |
CCL5 | Chemokine (C-C motif) ligand 5, RANTES | Adipose-derived MSCs | ADMSCs treated with TNBC CM | [6] |
COX2 | Cyclooxygenase 2, Prostaglandin synthase 2 | Adipose-derived MSCs | ADMSCs treated with TNBC CM | [6] |
CXCL1/GRO | CXC motif chemokine ligand 1, growth-related oncogene | TNBC cells | Secretome profiling of CM; TNBC cells cocultured with hBMECS; inhibition of IRE1 in TNBC cells | [7,18,19] |
GM-CSF | Granulocyte-macrophage colony-stimulating factor | TNBC cells | Inhibition of IRE1 in TNBC cells | [19] |
HIF-1α | Hypoxia-inducible factor-1 subunit alpha | Adipose-derived MSCs | ADMSCs treated with TNBC CM | [6] |
HMGA1 | High-mobility group A1 | TNBC cells and tumors | TNBC tumors | [20,21] |
IL-1β | Interleukin-1 beta | Macrophages, adipose-derived MSCs, TNBC cells | CM and patient serum in mouse model; ADMSCs treated with TNBC CM; TNBC cells in model of blood–brain barrier | [6,22,23] |
IL-6 | Interleukin-6 | TNBC cells; adipose-derived MSCs | Secretome profiling of CM; ADMSCs treated with TNBC CM; Inhibition of IRE1 in TNBC cells | [6,18,19] |
IL-8 | Interleukin-8 | TNBC cells | Secretome profiling of CM; Inhibition of IRE1 in TNBC cells | [18,19] |
LCN2 | Lipocalin-2 | Stromal cells | TNBC cells cocultured with four types of stromal cells | [24] |
PD-L1 | Programmed death ligand 1 | Adipose-derived MSCs | ADMSCs treated with TNBC CM | [6] |
PLAUR | suPAR, soluble urokinase receptor | TNBC cells | TNBC cells (inducible silencing of HMGA1) | [25] |
SAA1 | Serum amyloid A1 | TNBC cells | MS analysis of CM | [11] |
SLIT3 | Slit guidance ligand 3 | Fibroblasts | TNBC cells treated with CAF CM | [15] |
THBS1 | Thrombospondin 1 | TNBC cells | MS analysis of CM | [11] |
Growth Factors | ||||
BDNF | Brain-derived neurotrophic factor | Fibroblasts | Coculture of fibroblasts with TNBC cells | [12,13] |
END1 | Endothelin-1 | TNBC cells | CM from TNBC cell lines depleted of Syndecan-1 | [16] |
GRN | Granulin | TNBC cells | TNBC cell line depleted of LRP-1 | [26] |
NODAL | Nodal growth differentiation factor (TGFβ superfamily) | TNBC tumors | IHC of human tumors | [27] |
PLGF | Placental growth factor | Fibroblasts | Coculture of fibroblasts with TNBC cells | [12] |
TGFβ1 | Transforming growth factor beta 1 | TNBC cells | TNBC cell line depleted of LRP-1; MS analysis of CM | [11,26] |
TGFβ2 | Transforming growth factor beta 2 | TNBC cells | Inhibition of IRE1 in TNBC cells | [19] |
VEGF-A | Vascular endothelial growth factor A | TNBC cells and xenograft tumors; Adipose-derived MSCs | CM from TNBC cell lines depleted of Syndecan-1; interstitial fluid of xenograft tumors; ADMSCs treated with TNBC CM | [6,16,28] |
Protein | Aliases | Source | Evidence | Refs. |
---|---|---|---|---|
BGN | Biglycan | TNBC cells | MS analysis of CM | [11] |
CD44 | Cluster of differentiation 44 | TNBC cells | MS analysis of CM; CM and patient serum in mouse model | [11,22] |
CD109 | Cluster of differentiation 109 | TNBC cells | MS analysis of CM | [11] |
DAG1 | Dystroglycan | TNBC cells | MS analysis of CM | [11] |
DCN | Decorin | TNBC cells | MS analysis of CM | [11] |
ECM1 | Extracellular matrix protein 1 | TNBC cells | MS analysis of CM; TNBC cell line depleted of LRP-1 | [11,26] |
EFEMP1/FBLN3 | EGF-containing fibulin-like extracellular matrix protein 1, Fibulin 3 | TNBC cells | MS analysis of CM | [11] |
FBLN1 | Fibulin 1 | CAFs | TNBC cells treated with CAF CM | [15] |
FMOD | Fibromodulin | TNBC cells | MS analysis of CM | [11] |
IGFBP4 | Insulin-like growth factor-binding protein 4 | TNBC cells | MS analysis of CM | [11] |
IGFBP7 | Insulin-like growth factor-binding protein 7 | TNBC cells | MS analysis of CM | [11] |
IGFBP10/ Cyr61/CCN1 | Insulin-like growth factor-binding protein 10, Cysteine-rich angiogenic inducer 61, CCN1 | TNBC cells (exosomes) | Migration of TNBC cells decreased by neutralizing antibodies | [36] |
L1CAM | L1 cell adhesion molecule | TNBC cells | MS analysis of CM | [11] |
LGALS1 | Galectin 1 | TNBC cells | MS analysis of CM | [11] |
LGALS3BP | Galectin 3-binding protein | TNBC cells | MS analysis of CM | [11] |
LOXL2 | Lysyl oxidase-like 2 | TNBC cells | MS analysis of CM | [11] |
LTBP1 | Latent TGFβ-binding protein 1 | TNBC cells | MS analysis of CM | [11] |
NRCAM | Neuronal cell adhesion molecule | TNBC cells | MS analysis of CM | [11] |
P4HB | Protein disulfide-isomerase, prolyl 4-hydroxylase beta | TNBC cells | MS analysis of CM | [11] |
PLOD1 | Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 | TNBC cells | MS analysis of CM | [11] |
PPIB | Peptidyl-prolyl cis-trans isomerase B | TNBC cells | MS analysis of CM | [11] |
RELN | Reelin | TNBC cells | TNBC cells (knockdown of integrin alpha3) | [37] |
TF | Tissue factor | TNBC cells | CM from TNBC cell lines depleted of Syndecan-1 | [16] |
TLN1 | Talin 1 | TNBC cells | MS analysis of CM | [11] |
TNC | Tenascin C | TNBC cells | MS analysis of CM | [11] |
Protein | Aliases | Source | Evidence | Refs. |
---|---|---|---|---|
CTSD | Cathepsin D | TNBC cells | TNBC cells treated with tocotrienols (vitamin E) | [60] |
CTSZ | Cathepsin Z | TNBC cells | MS analysis of CM | [11] |
GGH | Gamma-glutamyl hydrolase | TNBC cells | MS analysis of CM | [11] |
PCSK9 | Proprotein convertase subtilisin/kexin type 9 | TNBC cells | MS analysis of CM | [11] |
PLAT | Tissue plasminogen activator | TNBC cells | TNBC cell line depleted of LRP-1 | [26] |
PLAU | uPA, urokinase plasminogen activators | TNBC cells; xenograft tumors | TNBC cells (inducible silencing of HMGA1); interstitial fluid of xenograft tumors | [25,28] |
PLG | Plasminogen | TNBC cells | TNBC cell line depleted of LRP-1 | [26] |
APLP2 | Amyloid-beta precursor-like protein 2 | TNBC cells | MS analysis of CM | [11] |
APP | Amyloid-beta precursor protein | TNBC cells | MS analysis of CM | [11] |
PI3 | Elafin, peptidase inhibitor 3 | TNBC cells | MS analysis of CM | [11] |
SERPINE1 | Serine protease inhibitor E1, plasminogen activator inhibitor 1 (PAI1) | TNBC cells; xenograft tumors | MS analysis of CM; interstitial fluid of xenograft tumors; TNBC cells (inducible silencing of HMGA1); TNBC cells treated with tocotrienols (vitamin E); TNBC cell line depleted of LRP-1 | [11,25,26,28,60] |
TIMP1 | Tissue inhibitor of metalloproteinases 1 | TNBC cells; xenograft tumors | MS analysis of CM; interstitial fluid of xenograft tumors | [11,28] |
TIMP2 | Tissue inhibitor of metalloproteinases 2 | TNBC cells | MS analysis of CM | [11] |
TIMP1, -2, -3 | Tissue inhibitor of metalloproteinases | TNBC cells | TNBC cell line depleted of LRP-1 | [26] |
Membrane and Extracellular Vesicle Proteins | ||||
---|---|---|---|---|
Protein | Aliases | Source | Evidence | Refs. |
ANXA2 | Annexin II, annexin A2 | TNBC cells | TNBC cell lines | [116] |
BCAP31 | B cell receptor-associated protein 31 | TNBC cells | TNBC cell line treated with Palbociclib | [117] |
CD151 | Cluster of differentiation 151 | TNBC tumors | Exosomes from TNBC patient serum | [118] |
IL-3Rα | Interleukin-3 receptor subunit α | TNBC tumors and cells | TNBC tumor expression and modulation of IL-3R-containing EVs | [119] |
ITGB4 | Integrin β4 | TNBC cells | TNBC cells in coculture with CAFs; exosomes from TNBC cells | [120,121] |
SPANXB1 | Sperm protein associated with the nucleus on the X chromosome B1 | TNBC tumors | Circulating EVs from TNBC patients | [122] |
TSPAN11 | Tetraspanin 11 | TNBC cells | TNBC cell line treated with Palbociclib | [117] |
UCHL1 | Ubiquitin carboxyl-terminal hydrolase isozyme L1 | TNBC tumors and cells | Exosomes, serum, and CM | [123] |
Peptide Hormones | ||||
FST | Follistatin | TNBC cells | TNBC cell line depleted of LRP-1 | [26] |
PENK | Proenkephalin | CAFs | TNBC cells treated with CAF CM | [15] |
Metabolic Proteins | ||||
ENO1 | Alpha-enolase | TNBC cells | MS analysis of CM | [11] |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase | TNBC cells | MS analysis of CM | [11] |
LDHA | Lactate dehydrogenase A | TNBC cells | MS analysis of CM | [11] |
LDHB | Lactate dehydrogenase B | TNBC cells | MS analysis of CM | [11] |
LPA | Lipoprotein A | TNBC cells | MS analysis of CM | [11] |
TXNIP | Thioredoxin-interacting protein | TNBC cells | TNBC cells cocultured with hBMECS | [7] |
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McHenry, P.R.; Prosperi, J.R. Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential. Int. J. Mol. Sci. 2023, 24, 2100. https://doi.org/10.3390/ijms24032100
McHenry PR, Prosperi JR. Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential. International Journal of Molecular Sciences. 2023; 24(3):2100. https://doi.org/10.3390/ijms24032100
Chicago/Turabian StyleMcHenry, Peter R., and Jenifer R. Prosperi. 2023. "Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential" International Journal of Molecular Sciences 24, no. 3: 2100. https://doi.org/10.3390/ijms24032100
APA StyleMcHenry, P. R., & Prosperi, J. R. (2023). Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential. International Journal of Molecular Sciences, 24(3), 2100. https://doi.org/10.3390/ijms24032100