Table 2 Summary of meta-analysis of included studies showing significant association of in vitro breast cancer cell behaviour and modulation of TRAF2/4/6.

From: TRAF6 as a potential target in advanced breast cancer: a systematic review, meta-analysis, and bioinformatics validation

Outcome

Intervention

Type of cell cultures (no. studies)

Subgroup (std.) mean difference (95% CI)

Overall (std.) mean difference (95% CI)

Statistical method

Test for heterogeneity

Test for overall effect

TRAF2

Migration

Pharmacological inhibition + 

MCF7 (2)

MDA-MB-231 (2)

MDA-MB-435 (2)

− 62.02 [− 82.69, − 41.35]

− 52.16 [− 72.11, − 32.20]

− 58.25 [− 78.05, − 38.44]

− 57.49 [− 66.95, − 48.02]

Mean Difference (IV, Random, 95% CI)

Tau2 = 111.52; Chi2 = 25.49, df = 5 (P = 0.0001); I2 = 80%

Z = 11.91 (P < 0.00001)

Genetic inhibition

MDA-MB-231 (2)

B16F10 (1)

− 59.97 [− 88.86, − 31.09]

− 24.12 [− 30.99, − 17.25]

− 46.88 [− 79.80, − 13.96]

Mean Difference (IV, Random, 95% CI)

Tau2 = 778.00; Chi2 = 30.10, df = 2 (P < 0.00001); I2 = 93%

Z = 2.79 (P = 0.005)

Invasion

Pharmacological inhibition *

MCF7 (2)

MDA-MB-231 (2)

MDA-MB-435 (2)

− 61.41 [− 92.43, − 30.40]

− 44.83 [− 68.12, − 21.53]

− 47.48 [− 73.02, − 21.94]

− 51.08 [− 64.23, − 37.94]

Mean Difference (IV, Random, 95% CI)

Tau2 = 247.97; Chi2 = 63.60, df = 5 (P < 0.00001); I2 = 92%

Z = 7.62 (P < 0.00001)

Genetic inhibition

MDA-MB-231 (2)

NA

− 45.54 [− 56.46, − 34.62]

Mean Difference (IV, Fixed, 95% CI)

Chi2 = 0.38, df = 1 (P = 0.54); I2 = 0%

Z = 8.17 (P < 0.00001)

Genetic upregulation

MDA-MB-231 (3)

ZR-75–30 (2)

2.65 [0.41, 4.89]

5.95 [1.70, 10.19]

3.37 [1.39, 5.35]

Std. Mean Difference (IV, Fixed, 95% CI)

Chi2 = 6.79, df = 4 (P = 0.15); I2 = 41%

Z = 3.33 (P = 0.0009)

Proliferation

Genetic upregulation

MDA-MB-231 (1)

ZR-75–30 (1)

2.61 [2.10, 3.12]

3.34 [2.98, 3.70]

3.00 [2.28, 3.71]

Mean Difference (IV, Random, 95% CI)

Tau2 = 0.22; Chi2 = 5.19, df = 1 (P = 0.02); I2 = 81%

Z = 8.23 (P < 0.00001)

Adhesion

Pharmacological inhibition £

MCF7 (2)

MDA-MB-231 (2)

MDA-MB-435 (2)

BT474 (2)

− 58.48 [− 76.86, − 40.11]

− 42.59 [− 62.58, − 22.60]

− 41.32 [− 62.61, − 20.02]

− 19.78 [− 30.75, − 8.82]

− 40.54 [− 52.83, − 28.26]

Mean Difference (IV, Random, 95% CI)

Tau2 = 287.52; Chi2 = 83.94, df = 7 (P < 0.00001); I2 = 92%

Z = 6.47 (P < 0.00001)

TRAF4

Migration

Pharmacological inhibition + 

MCF7 (2)

MDA-MB-231 (2)

MDA-MB-435 (2)

− 62.02 [− 82.69, − 41.35]

− 52.16 [− 72.11, − 32.20]

− 58.25 [− 78.05, − 38.44]

− 57.49 [− 66.95, − 48.02]

Mean Difference (IV, Random, 95% CI)

Tau2 = 111.52; Chi2 = 25.49, df = 5 (P = 0.0001); I2 = 80%

Z = 11.91 (P < 0.00001)

Genetic inhibition

MCF7 (1)

MDA-MB-231 (2)

− 309.10 [− 358.84, − 259.36]

− 459.60 [− 523.02, − 396.18]

− 407.97 [− 525.57, − 290.37]

Mean Difference (IV, Random, 95% CI)

Tau2 = 8896.64; Chi2 = 13.71, df = 2 (P = 0.001); I2 = 85%

Z = 6.80 (P < 0.00001)

Genetic upregulation

MCF7 (3)

NA

− 89.52 [− 139.93, − 39.12]

Mean Difference (IV, Random, 95% CI)

Tau2 = 1728.25; Chi2 = 16.94, df = 2 (P = 0.0002); I2 = 88%

Z = 3.48 (P = 0.0005)

Invasion

Pharmacological inhibition *

MCF7 (2)

MDA-MB-231 (2)

MDA-MB-435 (2)

− 61.41 [− 92.43, − 30.40]

− 44.83 [− 68.12, − 21.53]

− 47.48 [− 73.02, − 21.94]

− 51.08 [− 64.23, − 37.94]

Mean Difference (IV, Random, 95% CI)

Tau2 = 247.97; Chi2 = 63.60, df = 5 (P < 0.00001); I2 = 92%

Z = 7.62 (P < 0.00001)

Genetic inhibition

MDA-MB-231 (4)

NA

− 7.00 [− 10.05, − 3.96]

Mean Difference (IV, Random, 95% CI)

Tau2 = 6.67; Chi2 = 38.27, df = 3 (P < 0.00001); I2 = 92%

Z = 4.51 (P < 0.00001)

Adhesion

Pharmacological inhibition £

MCF7 (2)

MDA-MB-231 (2)

MDA-MB-435 (2)

BT474 (2)

− 58.48 [− 76.86, − 40.11]

− 42.59 [− 62.58, − 22.60]

− 41.32 [− 62.61, − 20.02]

− 19.78 [− 30.75, − 8.82]

− 40.54 [− 52.83, − 28.26]

Mean Difference (IV, Random, 95% CI)

Tau2 = 287.52; Chi2 = 83.94, df = 7 (P < 0.00001); I2 = 92%

Z = 6.47 (P < 0.00001)

TRAF6

Migration

Pharmacological inhibition

BT549 (3)

MCF7 (1)

MDA-MB-231 (4)

MDA-MB-231-BT (4)

− 5.60 [− 11.76, 0.56]

− 9.20 [− 18.23, − 0.17]

− 6.28 [− 11.63, − 0.93]

− 3.21 [− 5.33, − 1.08]

− 4.01 [− 5.75, − 2.27]

Mean Difference (IV, Fixed, 95% CI)

Tau2 = 2.56; Chi2 = 16.53, df = 11 (P = 0.12); I2 = 33%

Z = 4.52 (P < 0.00001)

Genetic inhibition

MCF7 (3)

NA

− 0.32 [− 0.65, 0.01]

Mean Difference (IV, Random, 95% CI)

Tau2 = 0.08; Chi2 = 476.58, df = 2 (P < 0.00001); I2 = 100%

Z = 1.92 (P = 0.05)

Genetic upregulation

MCF7 (3)

NA

0.25 [0.23, 0.27]

Mean Difference (IV, Fixed, 95% CI)

Chi2 = 1.85, df = 2 (P = 0.40); I2 = 0%

Z = 3.14 (P = 0.002)

Invasion

Pharmacological inhibition

BT549 (3)

MCF7 (1)

MDA-MB-231 (4)

MDA-MB-231-BT (4)

− 5.78 [− 12.04, 0.47]

− 9.50 [− 18.82, − 0.19]

− 5.62 [− 10.34, − 0.90]

− 1.36 [− 2.53, − 0.19]

− 2.80 [− 4.26, − 1.34]

Mean Difference (IV, Fixed, 95% CI)

Tau2 = 2.23; Chi2 = 19.22, df = 11 (P = 0.06); I2 = 43%

Z = 3.76 (P = 0.0002)

Proliferation

Pharmacological inhibition

BT549 (4)

MCF7 (4)

MDA-MB-231 (8)

− 5.78 [− 12.04, 0.47]

− 9.50 [− 18.82, − 0.19]

− 5.62 [− 10.34, − 0.90]

− 21.46 [− 30.40, − 12.51]

Mean Difference (IV, Random, 95% CI)

Tau2 = 321.80; Chi2 = 677.01, df = 15 (P < 0.00001); I2 = 98%

Z = 4.70 (P < 0.00001)

Genetic upregulation

MCF7 (1)

4T1 (3)

0.12 [0.09, 0.15]

0.38 [0.24, 0.52]

0.31 [0.12, 0.51]

Mean Difference (IV, Random, 95% CI)

Tau2 = 0.04; Chi2 = 158.59, df = 3 (P < 0.00001); I2 = 98%

Z = 3.19 (P = 0.001)

  1. The analysis shows the mean difference or standard mean difference of different studies comparing the effects of the TRAF6 pharmacological inhibition, genetic inhibition or upregulation on cell migration as assessed by trans-well assay or wound healing assay, cell invasion as assessed by trans-well assay and proliferation as assessed by cell viability assay. Std., standardised; IV, inverse-variance weighting; NA, not applicable. + Refers to studies using the same intervention which inhibit both TRAF2 and 4 on cell invasion, *refers to studies using the same intervention which inhibit both TRAF2 and 4 on cell invasion, £ intervention modulated the activity of both TRAF2 and TRAF4.
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