Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status
Abstract
:1. Introduction
2. Patient Population and Methods
2.1. Patient Population
2.2. Blood Samples, Serum 25-Hydroxyvitamin D Assay, and Plasma Cytokine Assays
2.3. Statistical Analysis
3. Results
Characteristics | All patients (n = 490) | ER-negative (n = 113) | ER-positive (n = 370) |
---|---|---|---|
Age at diagnosis, years, mean ± sd | 56.4 ± 12.9 | 52.3 ± 12.7 | 57.6 ± 12.8 |
Menopausal status, N (%) | |||
Premenopausal | 200 (40.8) | 53 (46.9) | 145 (39.2) |
Postmenopausal | 290 (59.2) | 60 (53.1) | 225 (60.8) |
Body mass index | |||
Normal (<25 kg/m2) | 145 (30.3) | 34 (30.3) | 111 (30.9) |
Overweight (25–29.9 kg/m2) | 166 (34.7) | 46 (41.1) | 118 (32.9) |
Obese (≥ 30 kg/m2) | 168 (35.0) | 32 (28.6) | 130 (36.2) |
Vitamin D status | |||
Sufficient (≥30.0 ng/ml) | 93 (19.0) | 22 (19.5) | 70 (18.9) |
Insufficient (20–29.9 ng/ml) | 195 (39.8) | 41 (36.3) | 149 (40.3) |
Deficient (<20 ng/ml) | 202 (41.2) | 50 (44.3) | 151 (40.8) |
Stage, N (%) | |||
I | 293 (59.8) | 50 (44.2) | 237 (64.1) |
II/IIIA | 177 (36.1) | 58 (51.3) | 119 (32.2) |
IIIB/IIIC/IV | 20 (4.1) | 5 (4.4) | 14 (3.8) |
Histological grade, N (%) | |||
I | 45 (9.3) | 1 (0.9) | 42 (11.5) |
II | 129 (26.7) | 15 (13.5) | 114 (31.1) |
III | 310 (64.0) | 95 (85.6) | 210 (57.4) |
3.1. Correlations between Levels of 25OHD and Cytokines/Ratios
3.2. Main Effects of 25OHD and Cytokines/Ratios on Cancer ER Status
3.3. Combinational Associations of 25OHD and Cytokines/Ratios on ER Status in Premenopausal Breast Cancer Patients
Variable | 25OHD | IL5 | IFNα2 | TNFα | IFNα2/IL4 | IFNα2/IL10 | IFNα2/CCL2 | IFNα2/CCL7 | IFNα2/CCL11 | IFNα2/TNFα | IL12p70/IL5 | IFNγ/IL5 | CXCL10/IL5 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
IL5 | 0.05 | |||||||||||||
IFNα2 | 0.08 | 0.40 *** | ||||||||||||
TNFα | 0.05 | 0.40 *** | 0.33 *** | |||||||||||
IFNα2/IL4 | −0.06 | 0.07 | 0.35 *** | 0.11 * | ||||||||||
IFNα2/IL10 | 0.04 | 0.23 *** | 0.81 *** | 0.22 *** | 0.42 *** | |||||||||
IFNα2/CCL2 | 0.09 | 0.38 *** | 0.97 *** | 0.28 *** | 0.32 *** | 0.78 *** | ||||||||
IFNα2/CCL7 | −0.03 | 0.12 ** | 0.66 *** | 0.04 | 0.41 *** | 0.60 *** | 0.63 *** | |||||||
IFNα2/CCL11 | 0.03 | 0.38 *** | 0.96 *** | 0.32 *** | 0.33 *** | 0.78 *** | 0.94 *** | 0.64 *** | ||||||
IFNα2/TNFα | 0.06 | 0.22 *** | 0.87 *** | −0.11 * | 0.32 *** | 0.73 *** | 0.87 *** | 0.70 *** | 0.84 *** | |||||
IL12p70/IL5 | 0.01 | −0.64 *** | 0.00 | 0.00 | 0.06 | 0.07 | 0.00 | −0.09 | −0.01 | −0.02 | ||||
IFNγ/IL5 | 0.03 | −0.82 *** | −0.18 *** | −0.15 *** | 0.03 | −0.06 | −0.18 *** | −0.14 ** | −0.18 *** | −0.12 ** | 0.77 *** | |||
CXCL10/IL5 | −0.07 | −0.96 *** | −0.38 *** | −0.31 *** | −0.07 | −0.24 *** | −0.38 *** | −0.12 ** | −0.36 *** | −0.24 *** | 0.63 *** | 0.81 *** | ||
TNFα/IL5 | −0.04 | −0.95 *** | −0.33 *** | −0.14 ** | −0.03 | −0.18 *** | −0.33 *** | −0.12 ** | −0.31 *** | −0.28 *** | 0.70 *** | 0.85 *** | 0.95 *** |
Cytokine/Ratio | Level | All women | Premenopausal women | Postmenopausal women | ||||||
---|---|---|---|---|---|---|---|---|---|---|
# ER− vs. ER+ | OR (95% CI) | p * | # ER− vs. ER+ | OR (95% CI) | p * | # ER− vs. ER+ | OR (95% CI) | p * | ||
25OHD | High | 52/188 | 1.00 | 23/85 | 1.00 | 29/103 | 1.00 | |||
Low | 61/182 | 1.24 (0.80–1.92) | 0.34 | 30/60 | 2.08 (1.05–4.11) | 0.04 | 31/122 | 0.78 (0.42–1.45) | 0.44 | |
IL5 | Low | 53/187 | 1.00 | 20/87 | 1.00 | 33/100 | 1.00 | |||
High | 60/183 | 1.25 (0.8–1.95) | 0.32 | 33/58 | 3.09 (1.51–6.29) | 0.002 | 27/125 | 0.7 (0.38–1.28) | 0.25 | |
IFNα2 | Low | 45/194 | 1.00 | 16/75 | 1.00 | 29/119 | 1.00 | |||
High | 68/176 | 1.57 (1.01–2.44) | 0.05 | 37/70 | 2.46 (1.22–4.95) | 0.01 | 31/106 | 1.15 (0.62–2.11) | 0.66 | |
TNFα | Low | 55/188 | 1.00 | 28/104 | 1.00 | 27/84 | 1.00 | |||
High | 58/182 | 1.38 (0.87–2.17) | 0.17 | 25/41 | 2.27 (1.14–4.51) | 0.02 | 33/141 | 0.74 (0.4–1.37) | 0.34 | |
IFNα2/IL4 | Low | 46/195 | 1.00 | 21/81 | 1.00 | 25/114 | 1.00 | |||
High | 67/175 | 1.54 (0.99–2.4) | 0.06 | 32/64 | 1.99 (1.01–3.94) | 0.05 | 35/111 | 1.19 (0.64–2.21) | 0.59 | |
IFNα2/IL10 | Low | 45/194 | 1.00 | 16/70 | 1.00 | 29/124 | 1.00 | |||
High | 68/176 | 1.65 (1.06–2.58) | 0.03 | 37/75 | 2.25 (1.11–4.54) | 0.02 | 31/101 | 1.43 (0.78–2.62) | 0.25 | |
IFNα2/CCL2 | Low | 45/194 | 1.00 | 15/68 | 1.00 | 30/126 | 1.00 | |||
High | 68/176 | 1.56 (0.99–2.44) | 0.05 | 38/77 | 2.44 (1.17–5.09) | 0.02 | 30/99 | 1.23 (0.67–2.26) | 0.51 | |
IFNα2/CCL7 | Low | 45/194 | 1.00 | 21/82 | 1.00 | 24/112 | 1.00 | |||
High | 68/176 | 1.65 (1.06–2.57) | 0.03 | 32/63 | 1.71 (0.87–3.37) | 0.12 | 36/113 | 1.5 (0.81–2.78) | 0.20 | |
IFNα2/CCL11 | Low | 45/193 | 1.00 | 17/70 | 1.00 | 28/123 | 1.00 | |||
High | 68/177 | 1.49 (0.95–2.32) | 0.08 | 36/75 | 1.87 (0.94–3.74) | 0.08 | 32/102 | 1.26 (0.69–2.32) | 0.45 | |
IFNα2/TNFα | Low | 39/200 | 1.00 | 14/70 | 1.00 | 25/130 | 1.00 | |||
High | 74/170 | 2.03 (1.29–3.2) | 0.002 | 39/75 | 2.36 (1.14–4.9) | 0.02 | 35/95 | 1.87 (1.01–3.46) | 0.05 | |
IL12p70/IL5 | High | 48/194 | 1.00 | 23/82 | 1.00 | 25/112 | 1.00 | |||
Low | 65/176 | 1.54 (0.99–2.4) | 0.06 | 30/63 | 1.83 (0.93–3.59) | 0.08 | 35/113 | 1.39 (0.75–2.56) | 0.30 | |
IFNγ/IL5 | High | 55/188 | 1.00 | 24/85 | 1.00 | 31/103 | 1.00 | |||
Low | 58/182 | 1.2 (0.77–1.87) | 0.41 | 29/60 | 2.24 (1.12–4.5) | 0.02 | 29/122 | 0.8 (0.44–1.46) | 0.47 | |
CXCL10/IL5 | High | 50/187 | 1.00 | 18/79 | 1.00 | 32/108 | 1.00 | |||
Low | 63/183 | 1.27 (0.82–1.98) | 0.29 | 35/66 | 2.28 (1.14–4.55) | 0.02 | 28/117 | 0.84 (0.46–1.54) | 0.57 | |
TNFα/IL5 | High | 52/191 | 1.00 | 20/85 | 1.00 | 32/106 | 1.00 | |||
Low | 61/179 | 1.34 (0.86–2.09) | 0.20 | 33/60 | 2.82 (1.39–5.72) | 0.004 | 28/119 | 0.83 (0.45–1.53) | 0.56 |
Cytokine/Ratio | Level | High 25OHD | Low 25OHD | RERI (95% CI) | P_additive | P_multiplicative | ||
---|---|---|---|---|---|---|---|---|
# ER− vs. ER+ | OR (95% CI) * | # ER− vs. ER+ | OR (95% CI) * | |||||
IL5 | Low | 9/52 | 1.00 | 14/33 | 2.97 (1.08–8.14) | 2.43 (−2.8–7.67) | 0.36 | 0.89 |
High | 11/35 | 1.98 (0.69–5.67) | 19/25 | 6.38 (2.29–17.81) | ||||
IFNα2 | Low | 4/44 | 1.00 | 19/41 | 5.41 (1.63–17.97) | −1.83 (−9.33-5.67) | 0.63 | 0.10 |
High | 12/31 | 5.11 (1.43–18.22) | 18/29 | 7.68 (2.25–26.23) | ||||
TNFα | Low | 13/54 | 1.00 | 10/31 | 1.42 (0.53–3.79) | 5.46 (−1.84–12.76) | 0.14 | 0.09 |
High | 15/50 | 1.44 (0.59–3.48) | 15/10 | 7.32 (2.44–21.98) | ||||
IFNα2/IL4 | Low | 11/51 | 1.00 | 12/34 | 1.71 (0.64–4.56) | 1.05 (−1.77–3.88) | 0.47 | 0.81 |
High | 10/30 | 1.77 (0.62–5.06) | 20/30 | 3.54 (1.4–8.93) | ||||
IFNα2/IL10 | Low | 6/41 | 1.00 | 17/44 | 2.86 (0.98–8.31) | 0.55 (−3.59–4.69) | 0.79 | 0.57 |
High | 10/29 | 2.78 (0.86–9) | 20/31 | 5.19 (1.76–15.27) | ||||
IFNα2/CCL2 | Low | 11/39 | 1.00 | 12/46 | 0.91 (0.35–2.42) | 1.04 (−0.84–2.91) | 0.28 | 0.40 |
High | 8/23 | 1.39 (0.45–4.26) | 22/37 | 2.34 (0.94–5.83) | ||||
IFNα2/CCL7 | Low | 6/50 | 1.00 | 17/35 | 3.6 (1.24–10.44) | −2.77 (−8.48–2.94) | 0.34 | 0.06 |
High | 15/32 | 4.49 (1.51–13.34) | 15/28 | 4.32 (1.42–13.12) | ||||
IFNα2/CCL11 | Low | 6/42 | 1.00 | 17/43 | 2.69 (0.92–7.87) | −0.49 (−4.66–3.68) | 0.82 | 0.37 |
High | 11/28 | 3.18 (0.99–10.17) | 19/32 | 4.37 (1.5–12.76) | ||||
IFNα2/TNFα | Low | 5/42 | 1.00 | 18/43 | 3.06 (0.99–9.45) | 0.53 (−3.87–4.93) | 0.81 | 0.53 |
High | 9/28 | 2.85 (0.83–9.8) | 21/32 | 5.43 (1.77–16.62) | ||||
IL12p70/IL5 | High | 11/49 | 1.00 | 12/36 | 1.63 (0.61–4.34) | 1.26 (−1.88–4.4) | 0.43 | 0.78 |
Low | 12/33 | 1.86 (0.7–4.97) | 18/27 | 3.75 (1.42–9.92) | ||||
IFNγ/IL5 | High | 11/50 | 1.00 | 12/35 | 1.77 (0.66–4.77) | 2.67 (−1.62–6.96) | 0.22 | 0.42 |
Low | 13/35 | 1.64 (0.62–4.39) | 17/25 | 5.09 (1.85–14.05) | ||||
CXCL10/IL5 | High | 9/48 | 1.00 | 14/37 | 1.95 (0.73–5.23) | 1.59 (−1.71–4.89) | 0.34 | 0.75 |
Low | 9/31 | 1.73 (0.59–5.12) | 21/29 | 4.28 (1.63–11.24) | ||||
TNFα/IL5 | High | 10/52 | 1.00 | 13/33 | 2.27 (0.84–6.17) | 2.4 (−1.78–6.58) | 0.26 | 0.63 |
Low | 10/33 | 1.63 (0.57–4.62) | 20/27 | 5.3 (2–14.08) |
4. Discussion
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Yao, S.; Hong, C.-C.; McCann, S.E.; Zirpoli, G.; Quan, L.; Gong, Z.; Johnson, C.S.; Trump, D.L.; Ambrosone, C.B. Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status. Cancers 2014, 6, 211-225. https://doi.org/10.3390/cancers6010211
Yao S, Hong C-C, McCann SE, Zirpoli G, Quan L, Gong Z, Johnson CS, Trump DL, Ambrosone CB. Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status. Cancers. 2014; 6(1):211-225. https://doi.org/10.3390/cancers6010211
Chicago/Turabian StyleYao, Song, Chi-Chen Hong, Susan E. McCann, Gary Zirpoli, Lei Quan, Zhihong Gong, Candace S. Johnson, Donald L. Trump, and Christine B. Ambrosone. 2014. "Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status" Cancers 6, no. 1: 211-225. https://doi.org/10.3390/cancers6010211