01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer
- Zeitschrift:
- BMC Cancer > Ausgabe 1/2017
Background
Methods
Patients
Tumor samples
Analysis of protein expression
Patients’ clinicopathological characteristics
Characteristics
|
Patients (n)
|
Patients (%)
|
---|---|---|
Age (years)
|
||
< 50
|
10
|
15.9
|
≥ 50
|
53
|
84.1
|
Unknown
|
-
|
-
|
Tumor size (cm)
|
||
<2
|
45
|
71.4
|
≥ 2
|
17
|
27.0
|
Unknown
|
1
|
1.6
|
Histological grade
|
||
G1
|
15
|
23.8
|
G2
|
22
|
34.9
|
G3
|
24
|
38.1
|
Unknown
|
2
|
3.2
|
HER2/neu status
|
||
Negative
|
39
|
61.9
|
Positive
|
23
|
36.5
|
Unknown
|
1
|
1.6
|
ER status
|
||
Negative
|
15
|
23.8
|
Positive
|
47
|
74.6
|
Unknown
|
1
|
1.6
|
PR status
|
||
Negative
|
14
|
22.2
|
Positive
|
48
|
76.2
|
Unknown
|
1
|
1.6
|
Regional lymph nodes
|
||
Negative
|
44
|
69.8
|
Positive
|
16
|
25.4
|
Unknown
|
3
|
4.8
|
Local relapse
|
||
Negative
|
50
|
79.4
|
Positive
|
6
|
9.5
|
Unknown
|
7
|
11.1
|
Metastatic event
|
||
Non-metastasis
|
45
|
71.4
|
Metastasis
|
11
|
17.5
|
Unknown
|
7
|
11.1
|
Statistical analysis
Results
Association of expression in TEpCs of OPG, TRAIL, RANKL, SDF-1, IL-6, and CCL-2 with patients’ clinicopathological characteristics
Characteristics
|
Ligands in TEpC
|
||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OPG
|
TRAIL
|
RANKL
|
SDF-1
|
IL-6
|
CCL-2
|
||||||||
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
||
Age (years)
|
<50
|
10.0
|
>0.999
|
2.2
|
0.657
|
70.0
|
>0.999
|
40.0
|
0.153
|
22.2
|
0.464
|
22.2
|
0.110
|
≥50
|
15.7
|
16.0
|
73.1
|
67.3
|
39.2
|
4.1
|
|||||||
Tumor size (cm)
|
<2
|
13.9
|
>0.999
|
17.1
|
>0.999
|
65.9
|
0.114
|
70.4
|
0.044*
|
42.9
|
0.236
|
7.3
|
>0.999
|
≥2
|
11.8
|
17.6
|
88.2
|
41.2
|
23.5
|
6.2
|
|||||||
Histological grade
|
G1
|
20.0
|
0.713
|
21.4
|
0.744
|
46.7
|
0.073
|
80.0
|
0.093
|
42.9
|
0.307
|
6.7
|
0.357
|
G2
|
10.0
|
20.0
|
80.9
|
66.7
|
45.0
|
0.0
|
|||||||
G3
|
12.5
|
13.0
|
79.2
|
45.8
|
25.0
|
13.0
|
|||||||
HER2/neu status
|
Negative
|
8.1
|
0.239
|
18.9
|
0.733
|
76.3
|
0.388
|
63.2
|
>0.999
|
39.5
|
0.780
|
2.9
|
0.287
|
Positive
|
21.7
|
14.3
|
65.2
|
60.9
|
33.33
|
13.6
|
|||||||
ER status
|
Negative
|
13.3
|
>0.999
|
7.7
|
0.429
|
80.0
|
0.523
|
40.0
|
0.064
|
42.9
|
0.753
|
20.0
|
0.049*
|
Positive
|
13.3
|
20.0
|
69.6
|
69.6
|
35.6
|
2.4
|
|||||||
PR status
|
Negative
|
14.3
|
>0.999
|
8.3
|
0.444
|
78.6
|
0.737
|
50.0
|
0.351
|
38.5
|
>0.999
|
7.1
|
>0.999
|
Positive
|
13.0
|
19.6
|
70.2
|
66.0
|
37.0
|
7.0
|
|||||||
Regional lymph nodes
|
Negative
|
11.6
|
0.666
|
25.0
|
0.048*
|
67.4
|
0.352
|
58.1
|
0.555
|
39.0
|
0.761
|
4.7
|
0.349
|
Positive
|
20.0
|
0.0
|
81.2
|
68.7
|
31.2
|
14.3
|
|||||||
Metastatic occurrence
|
Negative
|
20.9
|
0.180
|
21.4
|
0.664
|
70.4
|
0.707
|
59.1
|
>0.999
|
30.2
|
>0.999
|
2.4
|
0.109
|
Positive
|
18.2
|
10.0
|
81.8
|
63.6
|
40.0
|
18.2
|
|||||||
Local relapse
|
Negative
|
6.1
|
0.330
|
20.8
|
0.576
|
70.0
|
0.307
|
60.0
|
>0.999
|
38.8
|
0.284
|
4.3
|
0.266
|
Positive
|
20.0
|
0.0
|
100.0
|
60.0
|
0.0
|
20.0
|
Univariate
|
p-value
|
||
---|---|---|---|
Disease-free survival
|
Metastasis-free survival
|
Overall survival
|
|
Age
|
0.598
|
0.448
|
0.500
|
Tumor size
|
0.113
|
0.020*
|
0.069
|
Histological grade
|
0.178
|
0.291
|
0.207
|
HER2/neu status
|
0.536
|
0.293
|
0.103
|
ER status
|
0.336
|
0.191
|
0.175
|
PR status
|
0.691
|
0.946
|
0.521
|
Regional lymph nodes
|
0.595
|
0.805
|
0.620
|
OPG/TEpC
|
0.167
|
0.052
|
0.178
|
TRAIL/TEpC
|
0.465
|
0.648
|
0.304
|
RANKL/TEpC
|
0.156
|
0.267
|
0.307
|
SDF-1/TEpC
|
0.660
|
0.932
|
0.710
|
IL-6/TEpC CCL-2
|
0.873
|
0.710
|
0.487
|
CCL-2/TEpC
|
0.048*
|
0.071
|
0.507
|
TRAIL-R1/TEpC
|
0.536
|
0.339
|
0.626
|
TRAIL-R2/TEpC
|
0.894
|
0.749
|
0.392
|
TRAIL-R3/TEpC
|
0.009*
|
0.012*
|
0.015*
|
TRAIL-R4/TEpC
|
0.186
|
0.131
|
0.478
|
RANK/TEpC
|
0.546
|
0.991
|
0.804
|
CXCR-4/TEpC
|
0.164
|
0.255
|
0.175
|
IL-6R/TEpC
|
0.391
|
0.540
|
0.626
|
CCR-2/TEpC
|
0.013*
|
0.002*
|
0.049*
|
OPG/stromal cells
|
0.318
|
0.101
|
0.441
|
TRAIL/stromal cells
|
0.284
|
0.084
|
0.337
|
RANKL/stromal cells
|
0.139
|
0.052
|
0.222
|
SDF-1/stromal cells
|
0.792
|
0.734
|
0.306
|
IL-6/stromal cells CCL-2
|
0.218
|
0.093
|
0.168
|
CCL-2/stromal cells
|
0.104
|
0.076
|
0.505
|
Association of expression in TEpCs of TRAIL-R1–4, RANK, CXCR-4, IL-6R, and CCR-2 with patients’ clinicopathological characteristics
Characteristics
|
Receptors in TEpC
|
||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
TRAIL-R1
|
TRAIL-R2
|
TRAIL-R3
|
TRAIL-R4
|
RANK
|
CXCR-4
|
IL-6-R
|
CCR-2
|
||||||||||
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
||
Age (years)
|
<50
|
87.5
|
0.249
|
0.0
|
>0.999
|
40.0
|
0.729
|
80.0
|
0.175
|
30.0
|
0.176
|
50.0
|
0.259
|
75.0
|
0.042*
|
11.1
|
>0.999
|
≥50
|
63.5
|
9.6
|
34.0
|
54.7
|
55.8
|
73.1
|
31.3
|
12.0
|
|||||||||
Tumor size (cm)
|
<2
|
66.7
|
>0.999
|
9.3
|
>0.999
|
35.6
|
>0.999
|
57.8
|
>0.999
|
50.0
|
0.579
|
68.2
|
>0.999
|
31.6
|
0.365
|
11.9
|
>0.999
|
≥2
|
64.7
|
5.9
|
35.3
|
58.8
|
58.8
|
70.6
|
47.1
|
12.5
|
|||||||||
Histological grade
|
G1
|
71.4
|
0.397
|
13.3
|
0.245
|
33.3
|
>0.999
|
60.0
|
0.803
|
53.3
|
>0.999
|
66.7
|
0.941
|
38.5
|
0.078
|
20.0
|
0.597
|
G2
|
55.0
|
0.0
|
36.7
|
63.6
|
52.4
|
71.4
|
16.7
|
10.0
|
|||||||||
G3
|
75.0
|
12.5
|
37.5
|
54.2
|
50.0
|
66.7
|
50.0
|
8.7
|
|||||||||
HER2/neu status
|
Negative
|
59.5
|
0.255
|
5.4
|
0.361
|
25.6
|
0.054
|
51.3
|
0.190
|
52.6
|
>0.999
|
71.0
|
0.776
|
26.5
|
0.083
|
16.7
|
0.235
|
Positive
|
77.3
|
13.0
|
52.2
|
69.6
|
52.2
|
65.2
|
52.4
|
4.5
|
|||||||||
ER status
|
Negative
|
66.7
|
>0.999
|
13.3
|
0.590
|
53.3
|
0.125
|
60.0
|
>0.999
|
60.0
|
0.562
|
73.3
|
0.757
|
46.7
|
0.361
|
20.0
|
0.359
|
Positive
|
65.9
|
6.7
|
29.8
|
57.4
|
50.0
|
67.4
|
32.5
|
9.3
|
|||||||||
PR status
|
Negative
|
64.3
|
>0.999
|
14.3
|
0.581
|
42.9
|
0.539
|
57.1
|
>0.999
|
57.1
|
0.766
|
78.6
|
0.516
|
35.7
|
>0.999
|
14.3
|
>0.999
|
Positive
|
66.7
|
6.5
|
33.3
|
58.3
|
51.1
|
66.0
|
36.6
|
11.4
|
|||||||||
Regional lymph nodes
|
Negative
|
64.3
|
0.342
|
9.3
|
>0.999
|
36.4
|
>0.999
|
61.4
|
0.771
|
55.8
|
0.558
|
72.1
|
0.533
|
35.0
|
0.749
|
11.9
|
>0.999
|
Positive
|
80.0
|
6.7
|
37.5
|
56.2
|
43.7
|
62.5
|
42.9
|
13.3
|
|||||||||
Metastatic occurrence
|
Negative
|
66.7
|
0.108
|
4.6
|
0.502
|
26.7
|
0.032*
|
51.1
|
0.092
|
50.0
|
>0.999
|
70.4
|
0.473
|
30.8
|
0.171
|
4.8
|
0.003*
|
Positive
|
90.9
|
9.1
|
63.6
|
81.8
|
45.4
|
54.5
|
54.5
|
45.4
|
|||||||||
Local relapse
|
Negative
|
70.8
|
>0.999
|
4.1
|
0.257
|
31.4
|
0.323
|
56.9
|
>0.999
|
48.0
|
0.669
|
70.0
|
0.316
|
35.6
|
>0.999
|
14.6
|
0.601
|
Positive
|
80.0
|
20.0
|
60.0
|
60.0
|
60.0
|
40.0
|
40.0
|
0.0
|
Association of expression in spindle-shaped stromal cells of OPG, TRAIL, RANKL, SDF-1, IL-6, and CCL-2 with patients’ clinicopathological characteristics
Characteristics
|
Ligands in spindle-shaped stromal cells
|
||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OPG
|
TRAIL
|
RANKL
|
SDF-1
|
IL-6
|
CCL-2
|
||||||||
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
High expression %
|
p
|
||
Age (years)
|
<50
|
50.0
|
0.742
|
66.7
|
0.137
|
70.0
|
0.709
|
40.0
|
0.493
|
22.2
|
0.664
|
22.2
|
0.646
|
≥50
|
44.0
|
35.3
|
75.0
|
55.8
|
17.6
|
16.3
|
|||||||
Tumor size (cm)
|
<2
|
48.8
|
0.255
|
38.1
|
>0.999
|
68.2
|
0.193
|
56.8
|
0.391
|
21.4
|
0.483
|
19.5
|
0.708
|
≥2
|
31.2
|
41.2
|
88.2
|
41.2
|
11.8
|
12.5
|
|||||||
Histological grade
|
G1
|
60.0
|
0.336
|
35.7
|
0.518
|
60.0
|
0.491
|
66.7
|
0.042*
|
21.4
|
0.741
|
33.3
|
0.116
|
G2
|
35.0
|
50.0
|
76.2
|
66.7
|
20.0
|
5.3
|
|||||||
G3
|
39.1
|
33.3
|
79.2
|
33.3
|
12.5
|
17.4
|
|||||||
HER2/neu status
|
Negative
|
44.4
|
>0.999
|
44.7
|
0.272
|
78.9
|
0.368
|
57.9
|
0.302
|
18.4
|
>0.999
|
17.1
|
>0.999
|
Positive
|
43.5
|
28.6
|
65.2
|
43.5
|
19.0
|
18.2
|
|||||||
ER status
|
Negative
|
46.7
|
>0.999
|
42.9
|
0.761
|
80.0
|
0.738
|
53.3
|
>0.999
|
21.4
|
>0.999
|
20.0
|
>0.999
|
Positive
|
43.2
|
37.8
|
71.7
|
52.2
|
17.8
|
16.7
|
|||||||
PR status
|
Negative
|
42.9
|
>0.999
|
30.8
|
0.540
|
78.6
|
0.742
|
50.0
|
>0.999
|
15.4
|
>0.999
|
7.1
|
0.422
|
Positive
|
44.4
|
41.3
|
72.3
|
53.2
|
19.6
|
20.9
|
|||||||
Regional lymph nodes
|
Negative
|
46.1
|
0.547
|
41.5
|
>0.999
|
74.4
|
0.745
|
55.8
|
0.773
|
17.1
|
>0.999
|
19.0
|
0.724
|
Positive
|
35.7
|
37.5
|
68.7
|
50.0
|
18.7
|
14.3
|
|||||||
Metastatic occurrence
|
Negative
|
32.5
|
0.038*
|
34.9
|
0.072
|
65.9
|
0.146
|
47.3
|
0.745
|
11.6
|
0.163
|
9.1
|
0.049*
|
Positive
|
70.0
|
70.0
|
90.9
|
54.5
|
30.0
|
36.4
|
|||||||
Local relapse
|
Negative
|
39.6
|
>0.999
|
42.9
|
0.633
|
72.0
|
0.621
|
50.0
|
>0.999
|
16.3
|
0.612
|
14.9
|
>0.999
|
Positive
|
40.0
|
25.0
|
60.0
|
40.0
|
0.0
|
20.0
|
Univariate analysis of the association of classical prognostic markers with DFS, MFS, and OS
Multivariate analysis
Variables
|
HR
|
95% CI
|
p
|
|
---|---|---|---|---|
Disease-free survival
|
TRAIL-R3 in TEpC
|
3.566
|
1.164–10.920
|
0.026
|
Metastasis-free survival
|
Tumor size
|
8.210
|
2.013–33.477
|
0.003
|
CCR-2 in TEpC
|
10.257
|
2.569–40.947
|
0.001
|
|
Overall survival
|
TRAIL-R3 in TEpC
|
5.741
|
1.113–29.621
|
0.037
|