Abstract

Introduction: F-box proteins are the substrate-recognizing subunits of SKP1 (S-phase kinase-associated protein 1)–cullin1–F-box protein (SCF) E3 ligase complexes that play pivotal roles in multiple cellular processes, including cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Dysregulation of F-box proteins may lead to an unbalanced proteolysis of numerous protein substrates, contributing to progression of human malignancies. However, the prognostic values of F-box members, especially at mRNA levels, in breast cancer (BC) are elusive. Methods: An online database, which is constructed based on the gene expression data and survival information downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/), was used to investigate the prognostic values of 15 members of F-box mRNA expression in BC. Results: We found that higher mRNA expression levels of FBXO1, FBXO31, SKP2, and FBXO5 were significantly associated with worse prognosis for BC patients. While FBXO4 and β-TrCP1 were found to be correlated to better overall survival (OS). Conclusion: The associated results provide new insights into F-box members in the development and progression of BC. Further researches to explore the F-box protein-targetting reagents for treating BC are needed.

Introduction

Ubiquitin proteasome system (UPS) governs diverse cellular processes such as cell proliferation, cell cycle progression, transcription, and apoptosis through targetting specific substrate proteins for ubiquitylation and degradation. The ubiquitin-activating E1 enzyme, ubiquitin–conjugating E2 enzyme and ubiquitin-protein E3 ligase exert the multistep enzymatic processes to catalyze the ubiquitinated substrates. The SKP1–cullin1–F-box protein (SCF) E3 ligase complex, which is composed of the invariant components S-phase kinase-associated protein 1 (SKP1), the E3 ligase RBX1 (also known as ROC1) and cullin 1, as well as variable F-box proteins [1], is so far the best characterized E3 ligase family member [2]. The F-box proteins are able to bind to a distinct subset of substrates though its WD40 or leucine-rich domains and determine the substrate specificity of SCF complex [3]. Until now, 69 mammalian F-box proteins have been identified, they can be organized into three subclasses [4]: (i) the well-studied β-TRCP1, FBXW7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), and β-TRCP2 (also known as FBXW11), which contain WD40 repeat domains; (ii) FBXL family members, including SKP2 (also known as FBXL1), which contain leucine-rich repeat domains; and (iii) FBXO proteins. Owing to the pivotal and indispensable roles in cell cycle regulation that have been identified, the relationship between these proteins and tumorigenesis attract much attention [5].

Breast cancer (BC) is the most common malignant disease that causes the most cancer-related deaths amongst females worldwide [6]. According to the expression patterns of hormone and growth factor receptors, BCs are classified into four major molecular subtypes: luminal A and B, HER2-like, and basal-like. Due to the heterogeneous and high morbidity of disease, the death rates of BC remain high [7]. Therefore, the detailed molecular mechanism underlying the BC development and progression is important to be explored, and it is essential to identify novel targets for predicting or treating BCs. Amongst the 69 F-box proteins, only four members—FBXW7, SKP2, β-TrCP1, and β-TrCP2—have been extensively studied, and 15 of them are so far identified to play determined roles in cancers and they are grouped into four categories: tumor suppressive, oncogenic, context-dependent, or undetermined functions in cancer [4]. Nevertheless, the prognostic values of each individual F-box proteins, specially at the mRNA level in BCs are still elusive.

Kaplan–Meier plotter (KM plotter) database is constructed based on the gene expression data and survival information downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/) [8]. Owing to its ease of access to database, this online survival analysis tool has been widely used to analyze the prognostic values of individual genes in lung cancer, ovarian cancer, gastric cancer, and BC [9–12]. In the present study, we selected 15 well-identified members of F-box family to assess their prognostic values for BC. The relationship between F-box mRNA expression and clinical characteristics were also analyzed by KM plotter database.

Materials and methods

An online KM plotter database [8] was used to assess the prognostic values of 15 F-box members’ mRNA expression in BC as previously described [11]. The background database of this online survival analysis tool was established using gene expression data and survival information of 1809 patients (1402 BC patients with overall survival (OS) data) downloaded from GEO (Affymetrix HGU133A and HGU133+2 microarrays) [8]. These two microarrays are frequently used because these two arrays contain 22277 probe sets at nearly identical platforms. An overview of the clinical data is presented in Table 1 [13–25]. Each of 15 individual members of F-box members were entered into this online analysis database respectively (http://kmplot.com/analysis/index.php?p=service&cancer=breast), and Kaplan–Meier survival curves were acquired. Hazard ratio (HR), 95% confidence intervals (CI), and log rank P-values were also obtained on the webpages, and P-values of <0.05 were considered as statistically significant.

Table 1
Clinical characteristics of the microarray datasets used in the analysis
GEO ID Platform Number of patients Age (years) Tumor size (cm) ER+ Lymph node+ Grade 1 Grade 2 Grade 3 Relapse event Average relapase-free survival References 
GSE12276 GPL570 204 NA NA NA NA NA NA NA 204 2.2 ± 1.8 Bos et al. (2009) 
GSE16391 GPL570 55 61 ± 9 NA 55 33 35 18 55 3.0 ± 1.2 Desmedt et al. (2009) 
GSE12093 GPL96 136 NA NA 136 NA NA NA 20 7.7 ± 3.2 Zhang et al. (2009) 
GSE11121 GPL96 200 NA 2.1 ± 1 NA 58 136 35 46 7.8 ± 4.2 Schmidt et al. (2008) 
GSE9195 GPL570 77 64 ± 9 2.4 ± 1 77 36 14 20 24 13 7.8 ± 2.5 Loi et al. (2008) 
GSE7390 GPL96 198 46 ± 7 2.2 ± 0.8 134 NA 30 83 83 91 9.3 ± 5.6 Desmedt et al. (2007) 
GSE6532 GPL96 82 64 ± 10 2.5 ± 1.2 70 22 54 19 6.1 ± 3.1 Loi et al. (2007) 
GSE5327 GPL96 58 NA NA NA NA NA NA 11 6.8 ± 3.1 Minn et al. (2007) 
GSE4922 GPL96 69 2.2 12.17 Ivshina et al. (2006) 
GSE2494 GPL96 251 62 ± 14 2.2 ± 1.3 213 84 67 128 54 NA NA Miller et al. (2005) 
GSE2990 GPL96 102 58 ± 12 2.3 ± 1.1 73 15 27 20 36 40 6.6 ± 3.9 Sotirious et al. (2006) 
GSE2034 GPL96 286 NA NA 209 NA NA NA 107 6.5 ± 3.5 Wang et al. (2005) 
GSE1456 GPL96 159 NA NA NA NA 28 58 61 40 6.2 ± 2.3 Pawitan et al. (2005) 
Total  1809 57 ± 13 2.2 ± 1.1 968 190 227 534 312 646 6.4 ± 4.1  
GEO ID Platform Number of patients Age (years) Tumor size (cm) ER+ Lymph node+ Grade 1 Grade 2 Grade 3 Relapse event Average relapase-free survival References 
GSE12276 GPL570 204 NA NA NA NA NA NA NA 204 2.2 ± 1.8 Bos et al. (2009) 
GSE16391 GPL570 55 61 ± 9 NA 55 33 35 18 55 3.0 ± 1.2 Desmedt et al. (2009) 
GSE12093 GPL96 136 NA NA 136 NA NA NA 20 7.7 ± 3.2 Zhang et al. (2009) 
GSE11121 GPL96 200 NA 2.1 ± 1 NA 58 136 35 46 7.8 ± 4.2 Schmidt et al. (2008) 
GSE9195 GPL570 77 64 ± 9 2.4 ± 1 77 36 14 20 24 13 7.8 ± 2.5 Loi et al. (2008) 
GSE7390 GPL96 198 46 ± 7 2.2 ± 0.8 134 NA 30 83 83 91 9.3 ± 5.6 Desmedt et al. (2007) 
GSE6532 GPL96 82 64 ± 10 2.5 ± 1.2 70 22 54 19 6.1 ± 3.1 Loi et al. (2007) 
GSE5327 GPL96 58 NA NA NA NA NA NA 11 6.8 ± 3.1 Minn et al. (2007) 
GSE4922 GPL96 69 2.2 12.17 Ivshina et al. (2006) 
GSE2494 GPL96 251 62 ± 14 2.2 ± 1.3 213 84 67 128 54 NA NA Miller et al. (2005) 
GSE2990 GPL96 102 58 ± 12 2.3 ± 1.1 73 15 27 20 36 40 6.6 ± 3.9 Sotirious et al. (2006) 
GSE2034 GPL96 286 NA NA 209 NA NA NA 107 6.5 ± 3.5 Wang et al. (2005) 
GSE1456 GPL96 159 NA NA NA NA 28 58 61 40 6.2 ± 2.3 Pawitan et al. (2005) 
Total  1809 57 ± 13 2.2 ± 1.1 968 190 227 534 312 646 6.4 ± 4.1  

Results

Prognostic roles of F-box in all BC patients

We first examined the prognostic effects of 15 members of F-box mRNA in all BC patients by KM plotter database. As shown in Figure 1, FBXO1 (HR = 1.39 95%CI: 1.12–1.72, P=0.0025), FBXO31 (HR = 1.37 95%CI: 1.10–1.69, P=0.0040), SKP2 (HR = 1.85 95%CI: 1.49–2.30, P=0.0008), and FBXO5 (HR = 1.65 95%CI: 1.33–2.05, P=0.0004) were significantly associated with worse OS in all BC patients (Figure 1A–D). However, FBXO4 (HR = 0.56 95%CI: 0.41–0.77, P=0.0003) and β-TrCP1 (HR = 0.73 95%CI: 0.59–0.90, P=0.0034) were associated with better prognosis (Figure 1E,F). The mRNA expression levels of FBXW8, FBXL3, FBXO10, FBXO11, FBXO18, FBXO9, β-TrCP2, and FBXL10 were not correlated with OS in all BC patients (Supplementary Figure S1).

The prognostic values of the mRNA expression of F-box in all BCs

Figure 1
The prognostic values of the mRNA expression of F-box in all BCs

Overexpression of FBXO1 (A), FBXO31 (B), SKP2 (C), and FBXO5 (D) are significantly associated with worse OS in all BC patients. Overexpression of FBXO4 (E) and β-TrCP1 (F) are associated with better prognosis.

Figure 1
The prognostic values of the mRNA expression of F-box in all BCs

Overexpression of FBXO1 (A), FBXO31 (B), SKP2 (C), and FBXO5 (D) are significantly associated with worse OS in all BC patients. Overexpression of FBXO4 (E) and β-TrCP1 (F) are associated with better prognosis.

Prognostic roles of F-box members in different BC subtypes

Then, we respectively assessed the prognostic effects of F-box in BCs with different intrinsic subtypes. For luminal A type BC patients, FBXO1 (HR = 1.46 95%CI: 1.02–2.08, P=0.0358), SKP2 (HR = 1.80 95%CI: 1.25-2.57, P=0.0012), and FBXO5 (HR = 1.92 95%CI: 1.33–2.76, P=0.0004) were correlated to worse survival (Figure 2A–C). Whereas FBXW8 (HR = 0.55 95%CI: 0.33–0.92, P=0.0219) and β-TrCP1 (HR = 0.56 95%CI: 0.39–0.80, P=0.0014) were significantly associated with longer OS (Figure 2D,E). The rest members of F-box were not correlated to prognosis in luminal A type BC (Supplementary Figure S2).

The prognostic values of the mRNA expression of F-box in luminal A type BCs

Figure 2
The prognostic values of the mRNA expression of F-box in luminal A type BCs

The high expression of FBXO1 (A), SKP2 (B), and FBXO5 (C) are correlated to worse survival, and FBXW8 (D) and β-TrCP1 (E) are associated with longer OS in luminal A type BC patients.

Figure 2
The prognostic values of the mRNA expression of F-box in luminal A type BCs

The high expression of FBXO1 (A), SKP2 (B), and FBXO5 (C) are correlated to worse survival, and FBXW8 (D) and β-TrCP1 (E) are associated with longer OS in luminal A type BC patients.

In luminal B type BC patients, only high mRNA expression of FBXO4 was significantly associated with better survival, the HR was 0.38 (95%CI: 0.18-0.79, P=0.0070, Figure 3A). The remaining F-box members did not show any prognostic value in luminal B type BC patients (Supplementary Figure S3).

The prognostic values of some selected F-box in luminal B type, HER2-expressing or Basal-like BCs

Figure 3
The prognostic values of some selected F-box in luminal B type, HER2-expressing or Basal-like BCs

Survival curves of FBXO4 (A) are plotted for luminal B type BC patients. Survival curves of FBXW8 (B) and FBXL3 (C) are plotted for HER2-overexpressing BC patients. Survival curves of FBXW8 (D) are plotted for basal-like BC patients.

Figure 3
The prognostic values of some selected F-box in luminal B type, HER2-expressing or Basal-like BCs

Survival curves of FBXO4 (A) are plotted for luminal B type BC patients. Survival curves of FBXW8 (B) and FBXL3 (C) are plotted for HER2-overexpressing BC patients. Survival curves of FBXW8 (D) are plotted for basal-like BC patients.

In HER2-overexpressing BC, high mRNA expression of FBXW8 was associated with poor prognosis, the HR was 2.29 (95%CI: 0.99, 5.30), P=0.0475 (Figure 3B). However, FBXL3 (HR = 0.36, 95%CI: 0.16–0.84, P=0.0134) was significantly associated with better OS (Figure 3C). The rest of F-box members were not associated with prognosis in HER2-overexpressing BC patients (Supplementary Figure S4).

With regard to basal-like BC, none of the selected F-box members was associated with prognosis (Supplementary Figure S5). Only FBXW8 (HR = 0.52, 95%CI: 0.27–1.01, P=0.051) was modestly associated with better prognosis (Figure 3D).

Prognostic roles of F-box members in BC patients with different status of TP53

Furthermore, we assessed prognostic values of F-box members in BCs with different status of TP53. As shown in Table 2, only SKP2 (HR = 1.79, 95%CI: 0.92–3.49, P=0.0809) was modestly associated with worse survival for wild-TP53-type BCs, the other F-box members were not correlated with prognosis. In mutant-TP53-type BC, FBXL3 was significantly associated with longer OS, however, the other F-box members did not show any prognostic values.

Table 2
The association between the F-box members and the prognosis of BC with different p53 status
F-box family Affymetrix IDs p53 HR 95%CI P-value 
FBXW7 229419_at Mutant 1.99 (0.50, 7.98) 0.3193 
  Wild 
FBXO4 223493_at Mutant 1.20 (0.32, 4.48) 0.7888 
  Wild 1.88)/ 
FBXW8 231883_at Mutant 1.01 (0.26, 3.90) 0.9886 
  Wild 
FBXL3 225132_at Mutant 0.11 (0.01, 0.91) 0.0136 
  Wild 1.28 (0.55, 3.01) 0.5648 
FBXO1 204826_at Mutant 0.94 (0.44, 2.01) 0.8786 
  Wild 0.87 (0.46, 1.66) 0.6758 
FBXO10 227222_at Mutant 0.83 (0.22, 3.07) 0.7745 
  Wild 
FBXO11 222119_s_at Mutant 0.83 (0.38, 1.82) 0.6423 
  Wild 0.57 (0.29, 1.12) 0.1004 
FBXO18 224683_at Mutant 0.50 (0.13, 2.02) 0.3248 
  Wild 
FBXO31 219785_s_at Mutant 0.53 (0.24, 1.19) 0.1201 
  Wild 0.98 (0.51, 1.86) 0.9411 
SKP2 203625_at Mutant 0.70 (0.33, 1.52) 0.3681 
  Wild 1.79 (0.92, 3.49) 0.0809 
FBXO5 218875_at Mutant 1.02 (0.46, 2.27) 0.9562 
  Wild 1.24 (0.92, 3.49) 0.0809 
FBXO9 238472_at Mutant 1.93 (0.48, 7.73) 0.3471 
  Wild 
β-TrCP1 216091_s_at Mutant 1.47 (0.63, 3.43) 0.3684 
  Wild 1.01 (0.53, 1.92) 0.9799 
β-TrCP2 209455_at Mutant 0.79 (0.37, 1.71) 0.5514 
  Wild 1.52 (0.79, 2.92) 0.2037 
FBXL10 226215_s_at Mutant 1.43 (0.38, 5.41) 0.6004 
  Wild 
F-box family Affymetrix IDs p53 HR 95%CI P-value 
FBXW7 229419_at Mutant 1.99 (0.50, 7.98) 0.3193 
  Wild 
FBXO4 223493_at Mutant 1.20 (0.32, 4.48) 0.7888 
  Wild 1.88)/ 
FBXW8 231883_at Mutant 1.01 (0.26, 3.90) 0.9886 
  Wild 
FBXL3 225132_at Mutant 0.11 (0.01, 0.91) 0.0136 
  Wild 1.28 (0.55, 3.01) 0.5648 
FBXO1 204826_at Mutant 0.94 (0.44, 2.01) 0.8786 
  Wild 0.87 (0.46, 1.66) 0.6758 
FBXO10 227222_at Mutant 0.83 (0.22, 3.07) 0.7745 
  Wild 
FBXO11 222119_s_at Mutant 0.83 (0.38, 1.82) 0.6423 
  Wild 0.57 (0.29, 1.12) 0.1004 
FBXO18 224683_at Mutant 0.50 (0.13, 2.02) 0.3248 
  Wild 
FBXO31 219785_s_at Mutant 0.53 (0.24, 1.19) 0.1201 
  Wild 0.98 (0.51, 1.86) 0.9411 
SKP2 203625_at Mutant 0.70 (0.33, 1.52) 0.3681 
  Wild 1.79 (0.92, 3.49) 0.0809 
FBXO5 218875_at Mutant 1.02 (0.46, 2.27) 0.9562 
  Wild 1.24 (0.92, 3.49) 0.0809 
FBXO9 238472_at Mutant 1.93 (0.48, 7.73) 0.3471 
  Wild 
β-TrCP1 216091_s_at Mutant 1.47 (0.63, 3.43) 0.3684 
  Wild 1.01 (0.53, 1.92) 0.9799 
β-TrCP2 209455_at Mutant 0.79 (0.37, 1.71) 0.5514 
  Wild 1.52 (0.79, 2.92) 0.2037 
FBXL10 226215_s_at Mutant 1.43 (0.38, 5.41) 0.6004 
  Wild 

Prognostic roles of F-box members in BC patients with different pathological grades

Next, we assessed prognostic values of F-box members in different pathological grade BCs. We could see from the Table 3 that none of the F-box members was found to be associated with prognosis in grade I BC patients. While in grade II BC, FBXW7 (HR = 0.27, 95%CI: 0.07–1.02, P=0.0383) was correlated with better OS, FBXO1 (HR = 2.10, 95%CI: 1.34–3.30, P=0.0001) and SKP2 (HR = 1.56, 95%CI: 1.01–2.40, P=0.0420) were significantly associated with poor survival. However, the higher mRNA expression of FBXO4 (HR = 0.59, 95%CI: 0.35-0.99, P=0.0430) and FXBL3 (HR = 0.52, 95%CI: 0.31–0.88, P=0.0136) were associated with better survival for grade III BCs.

Table 3
Correlation of F-box with different pathological grade status of BC patients
F-box family Affymetrix IDs Grades HR 95%CI P-value 
FBXW7 229419_at 0.57 (0.05, 6.27) 0.6390 
  II 0.27 (0.07, 1.02) 0.0383* 
  III 1.32 (0.79, 2.21) 0.2833 
FBXO4 223493_at 1.66 (0.15, 18.35) 0.6780 
  II 1.10 (0.35, 3.48) 0.8711 
  III 0.59 (0.35, 0.99) 0.0430* 
FBXW8 231883_at 0.26 (0.02, 3.57) 0.2910 
  II 0.94 (0.30, 2.92) 0.9179 
  III 0.79 (0.48, 1.32) 0.3707 
FBXL3 225132_at 2.02 (0.18, 22.59) 0.5610 
  II 0.80 (0.25, 2.51) 0.6973 
  III 0.52 (0.31, 0.88) 0.0136* 
FBXO1 225132_at 0.73 (0.28, 1.87) 0.5070 
  II 2.10 (1.34, 3.30) 0.0001* 
  III 0.91 (0.66, 1.27) 0.5884 
FBXO10 227222_at 0.44 (0.04, 4.86) 0.4900 
  II 0.87 (0.28, 2.70) 0.8039 
  III 1.58 (0.95, 2.64) 0.0768 
FBXO11 222119_s_at 0.66 (0.26, 1.67) 0.3750 
  II 0.89 (0.58, 1.38) 0.6109 
  III 1.37 (0.98, 1.91) 0.0628 
FBXO18 224683_at 1.76 (0.16, 19.53) 0.6390 
  II 0.59 (0.18, 1.97) 0.3872 
  III 0.81 (0.49, 1.36) 0.4288 
FBXO31 219785_s_at 1.11 (0.45, 2.76) 0.8187 
  II 1.22 (0.79, 1.87) 0.3661 
  III 1.32 (0.95, 1.83) 0.0953 
SKP2 203625_at 1.59 (0.65, 3.92) 0.3078 
  II 1.56 (1.01, 2.40) 0.0420* 
  III 1.01 (0.73, 1.40) 0.9648 
FBXO5 218875_s_at 1.65 (0.67, 4.07) 0.2727 
  II 1.41 (0.92, 2.17) 0.1110 
  III 1.38 (0.99, 1.91) 0.0570 
FBXO9 238472_at 0.57 (0.05, 6.27) 0.6390 
  II 1.91 (0.58, 6.37) 0.2812 
  III 0.98 (0.58, 1.65) 0.9426 
β-TrCP1 216091_s_at 0.60 (0.24, 1.51) 0.2719 
  II 1.01 (0.66, 1.55) 0.9678 
  III 0.84 (0.60, 1.16) 0.2890 
β-TrCP2 209455_at 0.88 (0.35, 2.20) 0.7763 
  II 1.04 (0.68, 1.59) 0.8656 
  III 1.30 (0.94, 1.81) 0.1155 
FBXL10 226215_s_at 0.50 (0.04, 5.54) 0.5610 
  II 0.51 (0.15, 1.70) 0.2661 
  III 0.66 (0.39, 1.11) 0.1146 
F-box family Affymetrix IDs Grades HR 95%CI P-value 
FBXW7 229419_at 0.57 (0.05, 6.27) 0.6390 
  II 0.27 (0.07, 1.02) 0.0383* 
  III 1.32 (0.79, 2.21) 0.2833 
FBXO4 223493_at 1.66 (0.15, 18.35) 0.6780 
  II 1.10 (0.35, 3.48) 0.8711 
  III 0.59 (0.35, 0.99) 0.0430* 
FBXW8 231883_at 0.26 (0.02, 3.57) 0.2910 
  II 0.94 (0.30, 2.92) 0.9179 
  III 0.79 (0.48, 1.32) 0.3707 
FBXL3 225132_at 2.02 (0.18, 22.59) 0.5610 
  II 0.80 (0.25, 2.51) 0.6973 
  III 0.52 (0.31, 0.88) 0.0136* 
FBXO1 225132_at 0.73 (0.28, 1.87) 0.5070 
  II 2.10 (1.34, 3.30) 0.0001* 
  III 0.91 (0.66, 1.27) 0.5884 
FBXO10 227222_at 0.44 (0.04, 4.86) 0.4900 
  II 0.87 (0.28, 2.70) 0.8039 
  III 1.58 (0.95, 2.64) 0.0768 
FBXO11 222119_s_at 0.66 (0.26, 1.67) 0.3750 
  II 0.89 (0.58, 1.38) 0.6109 
  III 1.37 (0.98, 1.91) 0.0628 
FBXO18 224683_at 1.76 (0.16, 19.53) 0.6390 
  II 0.59 (0.18, 1.97) 0.3872 
  III 0.81 (0.49, 1.36) 0.4288 
FBXO31 219785_s_at 1.11 (0.45, 2.76) 0.8187 
  II 1.22 (0.79, 1.87) 0.3661 
  III 1.32 (0.95, 1.83) 0.0953 
SKP2 203625_at 1.59 (0.65, 3.92) 0.3078 
  II 1.56 (1.01, 2.40) 0.0420* 
  III 1.01 (0.73, 1.40) 0.9648 
FBXO5 218875_s_at 1.65 (0.67, 4.07) 0.2727 
  II 1.41 (0.92, 2.17) 0.1110 
  III 1.38 (0.99, 1.91) 0.0570 
FBXO9 238472_at 0.57 (0.05, 6.27) 0.6390 
  II 1.91 (0.58, 6.37) 0.2812 
  III 0.98 (0.58, 1.65) 0.9426 
β-TrCP1 216091_s_at 0.60 (0.24, 1.51) 0.2719 
  II 1.01 (0.66, 1.55) 0.9678 
  III 0.84 (0.60, 1.16) 0.2890 
β-TrCP2 209455_at 0.88 (0.35, 2.20) 0.7763 
  II 1.04 (0.68, 1.59) 0.8656 
  III 1.30 (0.94, 1.81) 0.1155 
FBXL10 226215_s_at 0.50 (0.04, 5.54) 0.5610 
  II 0.51 (0.15, 1.70) 0.2661 
  III 0.66 (0.39, 1.11) 0.1146 

Discussion

F-box protein is one of the core components of SCF multisubunit E3 ligase complex, it determines the substrate specificity of SCF complex by binding to substrates through WD40 or leucine-rich domains [3]. F-box family members are divided into three subclasses, including 10 FBXW proteins, 22 FBXL proteins, and 37 FBXO proteins. F-box proteins are implicated in multiple cellular processes, including cell proliferation, apoptosis, angiogenesis, and invasion via mediating degradation of numerous substrates [4]. In this study, by using an online survival analysis tool, we found that high mRNA expression of FBXO4 and β-TrCP1 were associated with better outcome for BCs, and FBXO1, FBXO31, FBXO5, and SKP2 were significantly correlated to worse prognosis.

FBXO4 is generally identified as a tumor suppressor, FBXO4-deficient mice will develop highly aggressive melanomas, as well as lymphomas, histolytic sarcomas, mammary and hepatocellular carcinomas [26,27]. Mutation or loss of FBXO4 impairs the dimerization of the SCFFbx4 ligase, resulting in accumulation of nuclear cyclin D1 and oncogenic transformation [28–30]. However, how FBXO4 determinates the cell fates of BC cells is unclear. We searched the Pubmed database and did not find any articles on the relationship between FBXO4 and BC. Hence, we used the KM plotter database to analyze the prognostic effect of FBXO4 in BC and found that high mRNA expression of FBXO4 was associated with longer OS for all BC patients. Additionally, high FBXO4 mRNA expression was correlated to better survival in luminal B and grade III BC patients.

β-TRCP1 and β-TRCP2 either exert their oncogenic or tumor suppressive roles depending on the specific cellular context(s). Interestingly, female mice with β-TRCP1−/− mammary glands exhibited hypoplastic phenotypes, which suggested that β-TRCP1 was critical for tissue development [31]. β-TRCP1 was significantly up-regulated in prostate cancer and hepatoblastoma [32], and high expression of β-TRCP1 at both mRNA and protein levels in colorectal cancer were correlated with poor clinical prognosis [33]. However, in gastric cancers, somatic mutation of β-TRCP1, which impaired ligase activity, contributed to tumor development and progression through β-catenin stabilization [34]. In TNBC cells, knockdown of β-TRCP1 reduced the cell proliferative ability [35], implicating a tumor suppressive role of β-TRCP1 in BC. Here, we showed that high mRNA expression of β-TRCP1 was associated with longer OS in luminal A type BC or all BC patients. On the other hand, β-TRCP2 also has tumor type-dependent roles in dominating tumorigenesis. Overexpression of β-TRCP2 was observed in a variety of human cancers, including prostate, breast, and gastric cancers [36]. Whereas mutation of β-TRCP2 in gastric cancer caused β-catenin accumulation, and contributed to carcinogenesis by activating WNT signaling pathway [37]. Inhibition of β-TRCP2 by miR-106b-25 cluster in non-small lung cancer cells promoted cell invasion and metastasis [38]. However, β-TRCP2 was not associated with prognosis in BC patients according to the current results analyzed by KM plotter database.

FBXO1, also known as cyclin F, meditates centrosome duplication and is critical for maintaining genome integrity, thus it has been regarded as an emerging tumor suppresser [39]. Knockout FBXO1 in MEFs leads to cell cycle defects [40]. In hepatocellular carcinoma, FBXO1 was down-regulated and low expression levels of FBXO1 were significantly associated with worse clinical characteristics and poorer prognosis [41]. Unexpectedly, we suggested an uncanonical function of FBXO1 exerted in BC, as we showed that high mRNA expression levels of FBXO1 were associated with worse survival in BC patients.

FBXO31 was regarded as an emerging tumor suppressor, which is often down-regulated in several human cancers, including BC, gastric cancer, and hepatocellular cancer [42–44]. FBXO31 was involved in DNA damage response for maintaining genomic stability. After DNA damage induced by genotoxic agents or γ-irradiation, phosphorylation of FBXO31 was increased immediately [45], then SCF/FBXO31 promoted MDM2 ubiquitination, resulting in accumulation of p53 and growth arrest [46]. Overexpression of FBXO31 in cancer cells inhibited cell growth and colon formation, and ectopic expression of FBXO31 significantly decreased tumor formation in xenograft nude mice [42–44]. However, overexpression of FBXO31 in lung cancer promoted cell growth and metastasis [47], and higher expression levels of FBXO31 predicted worse survival in esophageal squamous cell carcinoma [48]. Therefore, FBXO31 may also exert its role in tumorigenesis depending on tumor cell types. In our study, we used the KM plotter database to reveal that higher expression of FBXO31 mRNA was associated with poorer prognosis in BC patients.

The F-box protein SKP2 plays an oncogenic role in human cancers. Mechanistically, SKP2 facilitates ubiquitination and degradation of many tumor suppressors, such as p21, p27, p57, FOXO1, and others [2]. Furthermore, SKP2 enhances DNA damage response and promotes DNA double-strand break repair pathways in cancer cells [49]. As a result, SKP2 is up-regulated in several human cancers, including colorectal cancer [50], bladder cancer [51], BC [52,53], melanoma [54], prostate cancer [55], hepatocellular cancer [56], cervical cancer [49], and lymphoma [57]. In BC, SKP2 has been reported to correlate to poorer prognosis [58–60]. Additionally, immunohistochemical analysis indicated that overexpression of SKP2 were more frequently observed in ER-negative BC [53,59]. In our study, the higher expression of SKP2 mRNA was significantly associated with shorter OS in luminal A type BC patients. Previous results have indicated that SKP2 expression was associated with higher tumor grade in BCs or bladder cancers [51,59,60]. Interestingly, we showed that high mRNA expression of SKP2 was correlated to poor prognosis in grade II BC patients, but not in grade I or grade III BC patients.

FBXO5 is also suggested to play an emerging oncogenic role in human cancers. FBXO5 functions as an endogenous inhibitor of APC/C, which results in the stabilization of APC/C ubiquitin substrates, such as cyclin A, cylcin B, or Secure [61]. Up-regulation of FBXO5 in p53-deficient cells could promote cell proliferation, tetraploidy, and genomic instability [62]. By analysis of more than 1600 benign and malignant tumors, Lehman et al. [61] suggested that FBXO5 was strongly overexpressed in malignant tumors, rather than in benign tumors. Furthermore, overexpression of FBXO5 was associated with poor outcome in ovarian cancer [63], prostate cancer [64], and hepatocellular carcinoma [65]. In BC patients, overexpression of FBXO5 was significantly correlated with histologic grade and prognosis [66]. Consistently, our results demonstrated that FBXO5 had an oncogenic role in BC, higher expression of FBXO5 in mRNA level was significantly associated with poorer survival, especially in luminal A type BC patients.

FBXO11 was able to inhibit tumor cell growth and induced cell death by target BCL-6 for degradation [67], and deletion or mutation of FBXO11 in pancreatic cancer patients was associated with poor prognosis [68]. In BCs, FBXO11 restrained tumor initiation and metastasis by promoting SNAIL ubiquitylation and degradation, and overexpression of FBXO11 was correlated with longer metastasis-free survival [69,70]. However, our results did not find any relationship between the FBXO11 mRNA expression and OS in BC.

FBXW8 forms a functional E3 ligase complex with cullin 7 to exert a tumor suppressive role [4]. Ectopic expression of FBXW8 in choriocarcinoma JEG-3 cells increased the percentage of cells at S-phase and decreased the percentage of G2/M-phase cells [71], suggesting that FBXW8 was critical for cell growth. As FBXW8-meditated cyclin D1 and HPK1 degradation was necessary for cancer cell growth [71,72]. However, there is still no result about the prognostic role of FBXW8 in BC. Our results indicated that overexpression of FBXW8 mRNA was significantly associated with better prognosis in luminal A and basal-like BC patients, however, it was correlated with worse survival in HER2-overexpressiong BC patients.

An accumulation of pathological data have been proved that FBXW7 is a tumor suppressor by targetting various oncogenic proteins, such as Notch, cyclin E, c-Myc, and c-Jun, for degradation [73,74]. Interestingly, FBXW7 expressed in the host microenvironment also suppressed cancer metastasis depending on the FBXW7/NOTCH/CCL2 axis [75]. Hence, FBXW7 mutation, resulting in loss-of-function of FBXW7, was frequently observed amongst primary human cancers. Approximately 6% of human cancers were FBXW7 mutated, and 9% of primary endometrial cancers were FBXW7 mutated [76]. Reduced expression of FBXW7 has been reported to be correlated with worse outcomes in several human cancers, including gastric cancer [77], colorectal cancer [78], cervical squamous carcinoma [79], glioma [80], and prostate cancer [81]. For BCs, FBXW7 was significantly down-regulated, knockdown of FBXW7 in BC cells promoted cell proliferation, migration, and inhibited cell apoptosis [82,83]. Inactivation of FBXW7 by promoter-specific methylation was correlated with poorly differentiated BC [84]. FBXW7 mRNA expression was reduced in BC patients with high histological grade and hormone receptor-negative tumors [85]. A meta-analysis including 1900 patients indicated that the prognostic value of FBXW7 at mRNA level in BC was depending on ER status and molecular subtypes [86]. According to our results, increased mRNA expression of FBXW7 was associated with better OS only in grade II BC patients.

Amongst the large family members of F-box, only few members have been extensively studied. Here, we used the KM plotter database to assess the prognostic values of the selected 15 members of F-box mRNA expression in BC and demonstrated that FBXO1, FBXO31, SKP2, and FBXO5 were significantly associated with worse prognosis in BC patients. FBXO4 and β-TrCP1 were found to be correlated to better OS. These associated results provide new insights into F-box members in the development and progression of BC. Further studies are needed in order to get detailed understanding of functional characterization of each F-box member and determine whether they can be potential treatment targets of BC.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

The authors declare that there are no sources of funding to be acknowledged.

Author contribution

X.W. and S.Z. conceived and designed the research. T.Z., J.S., and X.W. performed the experiments and anlyzed the data. S.Z. and X.W. wrote the manuscript. All authors read and approved the final manuscript.

Abbreviations

     
  • APC/C

    anaphase-promoting complex/cyclosome

  •  
  • β-TrCP1

    β-transducin repeats containing proteins

  •  
  • BC

    breast cancer

  •  
  • BCL-6

    B-cell lymphoma 6 protein

  •  
  • CCL2

    chemokine (C-C motif) ligand 2

  •  
  • CI

    confidence interval

  •  
  • FBXO3

    F-box only protein 3

  •  
  • GEO

    gene expression omnibus

  •  
  • HPK1

    hematopoietic progenitor kinase1

  •  
  • HR

    hazard ratio

  •  
  • KM plotter

    Kaplan–Meier plotter

  •  
  • MEF

    mouse embryonic fibroblast

  •  
  • OS

    overall survival

  •  
  • SCFise

    SKP1–cullin1–F-box protein

  •  
  • SKP1

    S-phase kinase-associated protein 1

  •  
  • TNBC

    triple-negative breast cancer

  •  
  • WNT

    wingless/integrated

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Author notes

*

These authors contributed equally to this work.

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