In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. mTOR Complex Activity and Inhibitor Sensitivity in Human Breast Cancer Cell Lines
2.2. Glycolysis/Warburg Phenotype, Glutaminolysis and Lipid Metabolism in Human Breast Cancer Cell Lines
2.3. Metabolic Adaptation in MDA-MB231 Triple-Negative Human Breast Cancer Model
2.4. Clinicopathological Correlation between Selected mTOR Activity and Metabolic Markers in Human Breast Cancer Specimens
2.5. Analysis of In Situ mTOR and Metabolic Protein Expression: Correlation with Breast Cancer Prognosis
3. Discussion
4. Methods
4.1. Cell Cultures and In Vitro Treatments
4.2. In Vitro Toxicity Assays
4.3. Expression Analysis of Proteins by Western Blot Analyses or WES Simple on Samples of Human Breast Cancer Cell Lines
4.4. Intracellular Metabolite Concentration Measurement Using Liquid Chromatography–Mass Spectrometry
4.5. Doxorubicin Treatment of MDA-MB231 Xenografts
4.6. Immunohistochemistry on Human Tissues
4.7. mRNA Expression Data from the KM-Plotter Database
4.8. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Availability of Data and Materials
Ethics Approval and Consent to Participate
Abbreviations
ACSS2 | acyl-coenzyme A synthetase short-chain family member 2 |
Akt | protein kinase B |
BPTES | bis-2-(5-phenylacetoamido-1,3,4- thiadiazol-2-yl)-ethyl sulphide |
CDK4/6 | cyclin-dependent kinase 4 and 6 |
CPT1A | carnitine palmitoyltransferase 1A |
CST | Cell Signaling Technology |
DAB | 3:3′-diaminobenzidine |
DMFS | Distant metastasis-free survival |
DMSO | dimethyl sulfoxide |
ECL | enhanced chemiluminescence |
EGFR | epidermal growth factor receptor |
FA | fatty acid |
FASN | fatty acid synthase |
FBS | foetal bovine serum |
FFPE | formalin-fixed paraffin-embedded |
G6PDH | glucose-6-phosphate dehydrogenase |
GAC | glutaminase C |
GAPDH | glyceraldehyde 3-phosphate dehydrogenase |
GLUT1 | glucose transporter 1 |
GLS | glutaminase |
HER2 | human epidermal growth factor receptor 2 |
HK2 | hexokinase 2 |
HR | hormone receptor |
HRP | horseradish peroxidase |
IHC | immunohistochemistry |
KGA | kidney type glutaminase |
LDHA | lactate dehydrogenase A |
LDHB | lactate dehydrogenase B |
MCT | monocarboxylate transporter |
mTOR | mammalian target of rapamycin |
OS | overall survival |
OXPHOS | oxidative phosphorylation |
PARP | poly (ADP-ribose) polymerase |
PD-1 | programmed cell death protein 1 |
PD-L1 | programmed death-ligand 1 |
PI3K | phosphatidylinositol 3-kinase |
PI3KCA | phosphatidylinositol 3-kinase catalytic subunit A |
PKM2 | pyruvate kinase 2 |
PVDF | polyvinylidene difluoride |
RR | relative risk |
S6K1 | ribosomal protein S6 kinase beta-1 |
SRB | sulforhodamine B |
SREBP1 | sterol regulatory element-binding protein 1 |
TCA | tricarboxylic acid |
TNBC | triple-negative breast cancer |
VEGF | vascular endothelial growth factor |
β-F1-ATPase | β-F1-adenosine triphosphate synthase |
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p-S6 Expression | Rictor Expression | |||||||
---|---|---|---|---|---|---|---|---|
“Low” | “High” | 95% CI | p Value | “Low” | “High” | 95% CI | p Value | |
Age (years) | ||||||||
≤55 (n = 41) | 25 (61) | 16 (39) | 105.26–150.84 | 0.021 * | 17 (46) | 20 (54) | 157.00–196.51 | 0.666 |
>55 (n = 54) | 18 (36) | 32 (64) | 147.23–186.97 | 27 (53) | 24 (47) | 153.35–188.61 | ||
Subtype | ||||||||
n = 43 | n = 48 | 0.733 | n = 44 | n = 44 | 0.613 | |||
Luminal A (n = 16) | 7 (47) | 8 (53) | 103.10–196.90 | 6 (40) | 9 (60) | 167.88–213.45 | ||
Luminal B1 (n = 19) | 10 (56) | 8 (44) | 103.85–167.81 | 9 (47) | 10 (53) | 142.67–205.75 | ||
Luminal B2 (n = 22) | 12 (55) | 10 (45) | 106.69–172.40 | 10 (56) | 8 (44) | 154.70–204.19 | ||
HER2+ (n = 19) | 7 (37) | 12 (63) | 135.85–207.47 | 7 (41) | 10 (59) | 135.10–211.96 | ||
TNBC (n = 19) | 7 (41) | 10 (59) | 111.64–188.36 | 12 (63) | 7 (37) | 121.35–184.97 | ||
Grade | 0.256 | 0.441 | ||||||
1 (n = 7) | 3 (43) | 4 (57) | 78.66–218.48 | 4 (67) | 2 (33) | 125.89–224.11 | ||
2 (n = 38) | 13 (37) | 22 (63) | 140.59–188.55 | 15 (43) | 20 (57) | 168.06–205.09 | ||
3 (n = 50) | 27 (55) | 22 (45) | 117.37–160.38 | 25 (53) | 22 (47) | 143.90–182.91 | ||
pT Stage | 0.146 | 0.636 | ||||||
1 (n = 44) | 25 (58) | 18 (42) | 122.80–165.80 | 17 (43) | 23 (57) | 163.11–199.89 | ||
2 (n = 40) | 15 (39) | 23 (61) | 128.96–180.52 | 21 (57) | 16 (43) | 147.20–187.93 | ||
3 (n = 5) | 2 (50) | 2 (50) | 13.11–216.89 | 3 (60) | 2 (40) | 91.72–220.28 | ||
4 (n = 6) | 1 (17) | 5 (83) | 100.80–252.54 | 3 (60) | 2 (40) | 71.33–268.67 | ||
pN Stage | 0.596 | 0.829 | ||||||
x (n = 1) | 0 (0) | 1 (100) | not applicable | 1 (100) | 0 (0) | not applicable | ||
0 (n = 42) | 20 (50) | 20 (50) | 121.27–169.23 | 17 (45) | 21 (55) | 158.09–199.28 | ||
1 (n = 38) | 16 (44) | 20 (56) | 135.20–182.03 | 20 (56) | 16 (44) | 150.11–191.56 | ||
2 (n = 12) | 7 (58) | 5 (42) | 70.88–164.95 | 5 (45) | 6 (55) | 132.30–231.16 | ||
3 (n = 2) | 0 (0) | 2 (100) | 0.00–300.00 | 1 (50) | 1 (50) | 0.00–300.00 | ||
Metastasis (n = 38) | 8 (23) | 27 (77) | 141.92–189.23 | 0.0003 * | 21 (58) | 15 (42) | 144.52–186.59 | 0.278 |
W/O Metastasis (n = 57) | 35 (63) | 21 (37) | 119.47–159.46 | 23 (44) | 29 (56) | 162.10–195.59 |
GLS Expression | LDHA Expression | |||||||
---|---|---|---|---|---|---|---|---|
“Low” | “High” | 95% CI | p Value | “Low” | “High” | 95% CI | p Value | |
Age (years) | ||||||||
≤55 (n = 41) | 19 (53) | 17 (47) | 120.64–157.97 | 0.125 | 20 (56) | 16 (44) | 118.18–181.18 | 0.182 |
>55 (n = 54) | 17 (35) | 31 (65) | 145.22–180.20 | 18 (39) | 28 (61) | 140.57–196.17 | ||
Subtype | ||||||||
n = 36 | n = 48 | 0.296 | n = 38 | n = 44 | 0.001 * | |||
Luminal A (n = 16) | 4 (29) | 10 (71) | 145.67–204.33 | 11 (79) | 3 (21) | 50.42–126.73 | ||
Luminal B1 (n = 19) | 8 (42) | 11 (58) | 122.41–177.59 | 11 (69) | 5 (31) | 79.16–163.34 | ||
Luminal B2 (n = 22) | 8 (42) | 11 (58) | 123.65–195.83 | 8 (47) | 9 (53) | 117.49–190.75 | ||
HER2+ (n = 19) | 5 (33) | 10 (67) | 138.86–187.80 | 5 (31) | 11 (69) | 149.03–254.09 | ||
TNBC (n = 19) | 11 (65) | 6 (35) | 94.42–145.58 | 3 (16) | 16 (84) | 174.95–258.74 | ||
Grade | 0.118 | 0.0002 * | ||||||
1 (n = 7) | 1 (14) | 6 (86) | 141.73–229.70 | 6 (100) | 0 (0) | 6.26–107.07 | ||
2 (n = 38) | 12 (36) | 21 (64) | 141.17–185.19 | 20 (61) | 13 (39) | 104.10–155.29 | ||
3 (n = 50) | 23 (52) | 21 (48) | 122.66–156.43 | 12 (28) | 31 (72) | 169.65–226.86 | ||
pT Stage | 0.183 | 0.024 * | ||||||
1 (n = 44) | 12 (32) | 25 (68) | 157.23–192.50 | 22 (58) | 16 (42) | 102.66–164.44 | ||
2 (n = 40) | 18 (49) | 19 (51) | 119.88–156.33 | 13 (37) | 22 (63) | 154.45–215.84 | ||
3 (n = 5) | 2 (40) | 3 (60) | 126.44–197.56 | 3 (75) | 1 (25) | 0.00–300.00 | ||
4 (n = 6) | 4 (80) | 1 (20) | 0.00–192.14 | 0 (0) | 5 (100) | 173.80–246.20 | ||
pN Stage | 0.328 | 0.396 | ||||||
x (n = 1) | 0 (0) | 1 (100) | not applicable | 1 (100) | 0 (0) | not applicable | ||
0 (n = 42) | 13 (36) | 23 (64) | 128.99–176.29 | 17 (45) | 21 (55) | 129.80–186.25 | ||
1 (n = 38) | 15 (44) | 19 (56) | 139.45–172.90 | 17 (53) | 15 (47) | 116.32–189.93 | ||
2 (n = 12) | 6 (55) | 5 (45) | 108.82–178.45 | 2 (22) | 7 (78) | 141.79–273.76 | ||
3 (n = 2) | 2 (100) | 0 (0) | 0.00–227.06 | 1 (50) | 1 (50) | 0.00–300.00 | ||
Metastasis (n = 38) | 15 (45) | 18 (55) | 126.25–171.02 | 0.822 | 13 (39) | 20 (61) | 143.85–211.91 | 0.369 |
W/O Metastasis (n = 57) | 21 (41) | 30 (59) | 139.39–171.20 | 25 (51) | 24 (49) | 122.69–174.25 |
CPT1A Expression | FASN Expression | |||||||
---|---|---|---|---|---|---|---|---|
“Low” | “High” | 95% CI | p Value | “Low” | “High” | 95% CI | p Value | |
Age (years) | ||||||||
≤55 (n = 41) | 18 (51) | 17 (49) | 212.97–249.60 | 0.657 | 11 (30) | 26 (70) | 185.67–224.06 | 0.814 |
>55 (n = 54) | 27 (57) | 20 (43) | 207.78–239.46 | 15 (33) | 30 (67) | 197.95–234.05 | ||
Subtype | ||||||||
n = 45 | n = 37 | 0.454 | n = 26 | n = 56 | 0.208 | |||
Luminal A (n = 16) | 6 (40) | 9 (60) | 238.20–271.13 | 3 (20) | 12 (80) | 216.35–267.65 | ||
Luminal B1 (n = 19) | 9 (50) | 9 (50) | 208.35–252.76 | 5 (31) | 11 (69) | 162.74–243.51 | ||
Luminal B2 (n = 22) | 9 (53) | 8 (47) | 202.80–247.79 | 6 (30) | 14 (70) | 195.61–243.39 | ||
HER2+ (n = 19) | 11 (73) | 4 (27) | 162.57–240.76 | 3 (20) | 12 (80) | 198.33–248.33 | ||
TNBC (n = 19) | 10 (59) | 7 (41) | 190.01–254.69 | 9 (56) | 7 (44) | 141.00–194.00 | ||
Grade | 1.000 | 0.119 | ||||||
1 (n = 7) | 3 (50) | 3 (50) | 193.81–292.85 | 0 (0) | 6 (100) | 220.25–263.09 | ||
2 (n = 38) | 19 (56) | 15 (44) | 214.55–244.87 | 14 (41) | 20 (59) | 179.16–230.25 | ||
3 (n = 50) | 23 (55) | 19 (45) | 203.07–241.45 | 12 (29) | 30 (71) | 196.68–226.65 | ||
pT Stage | 0.625 | 0.154 | ||||||
1 (n = 44) | 19 (53) | 17 (47) | 215.93–249.90 | 8 (21) | 31 (79) | 202.23–239.82 | ||
2 (n = 40) | 20 (56) | 16 (44) | 210.03–244.41 | 14 (41) | 20 (59) | 180.26–222.09 | ||
3 (n = 5) | 2 (40) | 3 (60) | 107.99–300.00 | 2 (40) | 3 (60) | 150.92–273.08 | ||
4 (n = 6) | 4 (80) | 1 (20) | 129.45–238.55 | 2 (50) | 2 (50) | 76.99–300.00 | ||
pN Stage | 0.145 | 0.186 | ||||||
x (n = 1) | 0 (0) | 1 (100) | not applicable | 0 (0) | 1 (100) | not applicable | ||
0 (n = 42) | 24 (67) | 12 (33) | 205.83–238.34 | 13 (34) | 25 (66) | 181.63–223.11 | ||
1 (n = 38) | 16 (48) | 17 (52) | 210.70–249.30 | 8 (24) | 26 (76) | 197.75–238.14 | ||
2 (n = 12) | 5 (50) | 5 (50) | 168.28–273.72 | 3 (43) | 4 (57) | 179.18–257.96 | ||
3 (n = 2) | 0 (0) | 2 (100) | 142.94–300.00 | 2 (100) | 0 (0) | not applicable | ||
Metastasis (n = 38) | 16 (50) | 16 (50) | 198.99–243.51 | 0.503 | 12 (38) | 20 (62) | 172.64–220.49 | 0.467 |
W/O Metastasis (n = 57) | 29 (58) | 21 (42) | 216.92–244.08 | 14 (28) | 36 (72) | 205.38–235.02 |
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Petővári, G.; Dankó, T.; Tőkés, A.-M.; Vetlényi, E.; Krencz, I.; Raffay, R.; Hajdu, M.; Sztankovics, D.; Németh, K.; Vellai-Takács, K.; et al. In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy. Cancers 2020, 12, 2492. https://doi.org/10.3390/cancers12092492
Petővári G, Dankó T, Tőkés A-M, Vetlényi E, Krencz I, Raffay R, Hajdu M, Sztankovics D, Németh K, Vellai-Takács K, et al. In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy. Cancers. 2020; 12(9):2492. https://doi.org/10.3390/cancers12092492
Chicago/Turabian StylePetővári, Gábor, Titanilla Dankó, Anna-Mária Tőkés, Enikő Vetlényi, Ildikó Krencz, Regina Raffay, Melinda Hajdu, Dániel Sztankovics, Krisztina Németh, Krisztina Vellai-Takács, and et al. 2020. "In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy" Cancers 12, no. 9: 2492. https://doi.org/10.3390/cancers12092492