Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes
Abstract
Simple Summary
Abstract
1. Introduction
Interferons and Breast Cancer
2. Materials and Methods
Gene Expression Profiling and Data Processing
3. Results
3.1. GBP-1
3.2. GBP-5
3.3. GBP-2
4. Discussion
4.1. GBP-1
4.2. GBP-5
4.3. GBP-2
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Lines | Clinical Samples | Results | Reference |
---|---|---|---|
- | Breast cancer samples | GBP-1 and STAT1 are part of a 5 gene signature that correlates with improved RFS in all breast cancers. GBP-1 expression is highest in infiltrating cells but was also expressed in the tumor cells of recurrence-free patients. | Ascierto, 2013 [13] |
- | TNBC tumor samples | Subtyped TNBCs into 4 subgroups. Two subgroups were of basal histology. Basal-like Immune Activated (BLIA) tumors had elevated expression for genes for T-cell, B-cell, and NK activation. Further, IFN-γ stimulated genes. GBP-5 was the 3rd–5th most robustly induced gene in BLIA tumors, and GBP-1 was the 11th. BLIA tumors are predicted to have greater than 85% RFS over 10 years, much better than other forms of TNBC. | Burstein, 2015 [16] |
TS/A | - | Forced expression of GBP-1 in TS/A cells resulted in smaller tumors in immune competent mice. Not accompanied by decrease in infiltrating cells. Reduced Ki67. Reduced level of VEGF-A both in vitro and in vivo. | Lipnik, 2010 [30] |
MCF-7, SKBR3, MDA-MB-468, MDA-MB-436, MDA-MB-231, BT549, T47D | Breast cancer samples | Upregulated genes in TNBCs were analyzed for druggability using ChRMBL Studel. GBP-1 was ranked second in the upregulated genes based on druggability. KD of GBP-1 inhibited proliferation in a subgroup of TNBC cell lines. EGFR can drive GBP-1 expression in breast cancer. | Quintero, 2017 [20] |
SAS, HepG2, KB, MM102 cells | - | Cells made clinically cells radioresistant (CRR). All CRR cells expressed elevated GBP compared to parental cells. KD of GBP reduced radioresistance. | Fukumoto, 2014 [37] |
MDA-MB-231, MDA-MB-231-BM, SUM159PT | Human primary T-cells | Co-culturing activated T-cells with breast cancer cells increased their crossing of artificial blood brain barrier (BBB). GBP-1 was upregulated in the tumor cells after incubation with activated T-cells. KD of GBP-1 in tumor cells reduced crossing of the BBB after incubation with activated T-cells. | Mustafa, 2018 [38] |
Jurkat cells | Primary human T-cells | Silencing of GBP-1 increases T-cell spreading and surface expression of TCR/CD3 and CD45. Modulates early TCR signaling. | Forster, 2014 [33] |
Cell Lines | Clinical Samples | Results | Reference |
---|---|---|---|
- | TNBCs | GBP-5 is 5th most robustly induced gene in BLIA TNBC tumors with gene signatures of IFN-γ, B-cell, T-cell, and NK cell activation. Significantly improved survival compared to other TNBCs, particularly other basal TNBCs. | Burstein, 2015 [16] |
MDA-MB-231, Hs578T | TNBCs | High expression of GBP-5 correlated with improved RFS and PRS in TNBCs. GBP-5 not expressed in normal breast epithelial cells but expressed in 5/7 TNBC cell lines. Contributes to paclitaxel sensitivity. Suggest GBP-5 promotes TNBC protection by activating Akt/mTOR and inhibiting autophagy. | Cheng, 2021 [26] |
MDA-MB-231, Hs578T | TNBCs | GBP-5 expression correlates with poor prognosis in TNBCs. KD of GBP-5 inhibited cell migration and activity from both GAS and NF-kB promoter elements. | Cheng, 2021 [27] |
- | Breast Cancer Samples | Mutations in tumors with high PD1 and PD-L1 were associated with GBP-5 expression and good prognosis. Also associated with immune infiltration of the tumors. | Cimas, 2020 [28] |
Cell Lines | Clinical Samples | Results | Reference |
---|---|---|---|
766 node negative breast cancers | - | Elevated GBP-2 correlated with longer time to distant metastasis in highly proliferating ER+ tumors with infiltrating T-cells (as judged by gene signature). | Godoy, 2014 [22] |
MDA-MB-231 and MDA-MB-436 | - | GBP-2 interacts with Drp1 to both inhibit mitochondrial fission and cell migration. | Zhang, 2017 [23] |
4T1, 67NR murine breast cancer cells | - | GBP-2 inhibits cell migration by inhibiting Rac1 activation and activating CDC42 and RhoA. Inhibits invadosome formation. | Nyabuto, 2021 [24] |
NIH 3T3 fibroblasts, B16 melanoma | - | GBP-2 inhibits cell spreading downstream of integrins, PDGF, and TNF-α treatment. Inhibits activation of Rac1 and PI3-K when cells plated on fibronectin. | Messmer-Blust, 2010 [40] |
NIH3T3 cells | - | GBP-2 inhibits TNF-α induction of matrix metalloprotease-9 (MMP-9) by inhibiting the binding of NF-κB p65 to the MMP-9 promoter. | Balasubramanian, 2011 [41] |
TE-1 squamous cell carcinoma cells | - | GBP-2 is a p53 responsive gene. | Guimaraes, 2009 [42] |
- | Breast cancer and normal breast tissue, plasma | Levels of GBP-2 are reduced in breast tumors compared to normal breast tissue. GBP-2 is reduced in TNBC tumors, higher stages of breast cancers, and in node positive tumors compared to other breast tumors. The GBP-2 promoter in about 87% of breast cancers was methylated. GBP-2 was downregulated in 73% of breast cancers, 26% had normal GBP-2 expression, and none showed elevation of GBP-2. The methylation status of the GBP-2 promoter in tumors matched with the methylation status of cell free DNA isolated from the plasma. GBP-2 promoter was methylated in 100% of stage III or IV breast tumors. | Rahvar, 2020 [25] |
GBP-1 | Affymetrix Probe Sets | ||
---|---|---|---|
202269_x_at | 231577_s_at | 202270_at | |
Recurrence-Free Survival | |||
All Breast Cancers | HR = 1.26 (1.14–1.39), p = 9.1 × 10−6 | HR = 1.21 (1.04–1.41), p = 0.012 | HR = 1.19 (1.07–1.31), p = 0.00088 |
ER+ | HR = 1.02 (0.87–1.19), p = 0.83 | HR = 1.18 (0.89–1.58), p = 0.25 | HR = 1 (0.86–1.17), p = 0.97 |
ER+/HER2− | HR = 1.02 (0.86–1.2), p = 0.85 | HR = 1.1 (0.8–1.51), p = 0.55 | HR = 1.1 (0.93–1.3), p = 0.28 |
HER2+ | HR = 0.87 (0.7–1.08), p = 0.19 | HR = 1 (0.74–1.35), p = 1 | HR = 0.69 (0.55–0.86), p = 00081 |
ER− | HR = 0.59 (0.47–0.76), p = 2 × 10−5 | HR = 0.58 (0.4–0.85), p = 0.0042 | HR = 0.58 (0.46–0.74), p = 1 × 10−5 |
TNBC | HR = 0.5 (0.35–0.73), p = 0.00025 | HR = 0.31 (0.17–0.59), p = 0.00016 | HR = 0.45 (0.31–0.66), p = 2.1 × 10−5 |
Overall Survival | |||
All Breast Cancers | HR = 0.96 (0.79–1.15), p = 0.63 | HR = 0.91 (0.7–119), p = 0.5 | HR = 1.03 (0.85–1.24), p = 0.75 |
ER+ | HR = 1 (0.72–1.38), p = 0.99 | HR = 0.94 (0.46–1.96), p = 0.88 | HR = 1.08 (0.78–1.49), p = 0.64 |
ER+/HER2− | HR = 1.05 (0.73–1.5), p = 0.81 | HR = 0.92 (0.39–2.17), p = 0.85 | HR = 0.66 (0.45–0.95), p = 0.023 |
HER2+ | HR = 0.7 (0.49–1.01), p = 0.58 | HR = 0.9 (0.55–1.49), p = 0.69 | HR = 1.12 (0.78–1.62), p = 0.53 |
ER− | HR = 0.55 (0.37–0.82), p = 0.0033 | HR = 0.59 (0.35–0.98), p = 0.039 | HR = 0.55 (0.37–0.82), p = 0.003 |
TNBC | HR = 0.35 (0.17–0.72), p = 0.003 | HR = 0.36 (0.16–0.78), p = 0.0071 | HR = 0.49 (0.25–0.98), p = 0.039 |
Distant Metastasis-Free Survival | |||
All Breast Cancers | HR = 1.15 (0.99–1.34), p = 0.072 | HR = 1.07 (0.82–1.39), p = 0.63 | HR = 1.16 (1–1.36), p = 0.053 |
ER+ | HR = 1.13 (0.86–1.49), p = 0.37 | HR = 2.14 (0.98–4.65), p = 0.05 | HR = 0.99 (0.76–1.31), p = 0.96 |
ER+/HER2− | HR = 1.09 (0.81–1.47), p = 0.58 | HR = 1.91 (0.69–5.29), p = 0.2 | HR = 1 (0.74–1.35), p = 0.99 |
HER2+ | HR = 0.64 (0.45–0.89), p = 0.0083 | HR = 0.86 (0.54–1.35), p = 0.51 | HR = 0.73 (0.53–1.03), p = 0.07 |
ER− | HR = 0.58 (0.42–0.79), p = 0.00062 | HR = 0.61 (0.38–0.98), p = 0.04 | HR = 0.58 (0.42–0.79), p = 0.00059 |
TNBC | HR = 0.58 (0.38–0.9), p = 0.015 | HR = 0.47 (0.25–0.88), p = 0.017 | HR = 0.52 (0.34–0.81), p = 0.003 |
GBP-5 | Affymetrix Probe Sets | |
---|---|---|
229625_at | 23581_at | |
Recurrence-Free Survival | ||
All Breast Cancers | HR = 0.79 (0.68–0.92), p = 0.002 | HR = 0.78 (0.67–0.91), p = 0.0015 |
ER+ | HR = 1.04 (0.78–1.38), p = 0.81 | HR = 1.05 (0.79–1.39), p = 0.76 |
ER+/HER2− | HR = 1.1 (0.8–1.51), p = 0.55 | HR = 1.02 (0.75–1.4), p = 0.9 |
HER2+ | HR = 0.58 (0.43–0.8), p = 0.00054 | HR = 0.59 (0.43–0.8), p = 0.00057 |
ER− | HR = 0.56 (0.39–0.82), p = 0.0087 | HR = 0.56 (0.39–0.82), p = 0.0088 |
TNBC | HR = 0.42 (0.23–0.76), p = 0.0032 | HR = 0.46 (0.26–0.83), p = 0.0088 |
Overall Survival | ||
All Breast Cancers | HR = 0.7 (0.53–0.92), p = 0.009 | HR = 0.72 (0.55–0.94), p = 0.017 |
ER+ | HR = 0.59 (0.28–1.25), p = 0.17 | HR = 0.8 (0.39–1.67), p = 0.55 |
ER+/HER2− | HR = 0.63 (0.26–1.49), p = 0.28 | HR = 0.72 (0.3–1.72), p = 0.46 |
HER2+ | HR = 0.68 (0.41–1.13), p = 0.14 | HR = 0.6 (0.36–0.99), p = 0.045 |
ER− | HR = 0.52 (0.31–0.88), p = 0.012 | HR = 0.4 (0.23–0.68), p = 0.00043 |
TNBC | HR = 0.4 (0.19–0.86), p = 0.016 | HR = 0.41 (0.19–0.87), p = 0.017 |
Distant Metastasis-Free Survival | ||
All Breast Cancers | HR = 0.91 (0.7–1.19), p = 0.5 | HR = 0.96 (0.73–1.24), p = 0.74 |
ER+ | HR = 1.32 (0.62–2.79), p = 0.47 | HR = 1.37 (0.65–2.9), p = 0.41 |
ER+/HER2− | HR = 1.17 (0.43–3.15), p = 0.76 | HR = 1.06 (0.4–2.82), p = 0.91 |
HER2+ | HR = 0.74 (0.47–1.17), p = 0.2 | HR = 0.74 (0.47–1.17), p = 0.19 |
ER− | HR = 0.53 (0.33–0.86), p = 0.0082 | HR = 0.61 (0.38–0.98), p = 0.09 |
TNBC | HR = 0.48 (0.26–0.9), p = 0.02 | HR = 0.61 (0.33–1.13), p = 0.11 |
GBP-2 | Affymetrix Probe Sets | |
---|---|---|
202748_at | 242907_at | |
Recurrence-Free Survival | ||
All Breast Cancers | HR = 0.84 (0.76–0.93), p = 7 × 10−4 | HR = 0.72 (0.62–0.84), p = 2.8 × 10−5 |
ER+ | HR = 0.86 (0.74–1.01), p = 0.061 | HR = 0.97 (0.72–1.29), p = 0.81 |
ER+/HER2− | HR = 0.83 (0.7–0.98), p = 0.031 | HR = 0.88 (0.65–1.21), p = 0.45 |
HER2+ | HR = 0.77 (0.62–0.96), p = 0.022 | HR = 0.85 (0.63–1.15), p = 0.3 |
ER− | HR = 0.73 (0.57–0.93), p = 0.0094 | HR = 0.73 (0.57–0.93), p = 0.0095 |
TNBC | HR = 0.59 (0.41–0.86), p = 0.0048 | HR = 0.34 (0.18–0.64), p = 0.00045 |
Overall Survival | ||
All Breast Cancers | HR = 0.74 (0.61–0.898), p = 0.0014 | HR = 0.6 (0.46–0.79), p = 0.00019 |
ER+ | HR = 0.75 (0.55–1.04), p = 0.085 | HR = 0.49 (0.23–1.05), p = 0.061 |
ER+/HER2− | HR = 0.72 (0.5–1.03), p = 0.071 | HR = 0.44 (0.18–1.09). p = 0.068 |
HER2+ | HR = 0.82 (0.57–1.17), p = 0.27 | HR = 0.89 (0.54–1.47), p = 0.64 |
ER− | HR = 0.64 (0.43–0.95), p = 0.026 | HR = 0.64 (0.43–0.95), p = 0.027 |
TNBC | HR = 0.39 (0.19–0.79), p = 0.0069 | HR = 0.34 (0.16–0.75), p = 0.0052 |
Distant Metastasis-Free Survival | ||
All Breast Cancers | HR = 0.78 (0.67–0.91), p = 0.0014 | HR = 0.81 (0.62–1.06), p = 0.13 |
ER+ | HR = 0.65 (0.49–0.86), p = 0.0022 | HR = 0.84 (0.39–1.78), p = 0.64 |
ER+/HER2− | HR = 0.66 (0.49–0.9), p = 0.0079 | HR = 0.66 (0.49–0.9), p = 0.0079 |
HER2+ | HR = 0.73 (0.52–1.02), p = 0.065 | HR = 0.9 (0.57–1.42), p = 0.65 |
ER− | HR = 0.72 (0.53–0.98), p = 0.038 | HR = 0.75 (0.47–1.2), p = 0.23 |
TNBC | HR = 0.58 (0.37–0.9), p = 0.013 | HR = 0.42 (0.22–0.8), p = 0.0064 |
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Hunt, E.N.; Kopacz, J.P.; Vestal, D.J. Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes. Cancers 2022, 14, 2794. https://doi.org/10.3390/cancers14112794
Hunt EN, Kopacz JP, Vestal DJ. Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes. Cancers. 2022; 14(11):2794. https://doi.org/10.3390/cancers14112794
Chicago/Turabian StyleHunt, Erin N., Jonathan P. Kopacz, and Deborah J. Vestal. 2022. "Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes" Cancers 14, no. 11: 2794. https://doi.org/10.3390/cancers14112794
APA StyleHunt, E. N., Kopacz, J. P., & Vestal, D. J. (2022). Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes. Cancers, 14(11), 2794. https://doi.org/10.3390/cancers14112794