Breast Cancer Research and Treatment

, Volume 139, Issue 2, pp 477–488 | Cite as

Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers

  • Chi-Chen Hong
  • Song Yao
  • Susan E. McCann
  • Ree Y. Dolnick
  • Paul K. Wallace
  • Zhihong Gong
  • Lei Quan
  • Kelvin P. Lee
  • Sharon S. Evans
  • Elizabeth A. Repasky
  • Stephen B. Edge
  • Christine B. Ambrosone


Immune signatures in breast tumors differ by estrogen receptor (ER) status. The purpose of this study was to assess associations between ER phenotypes and circulating levels of cytokines that co-ordinate cell-mediated [T-helper type 1 (Th1)] and humoral [T-helper type 2 (Th2)] immunity. We conducted a case–case comparison of 523 women with newly diagnosed breast cancer to evaluate associations between 27 circulating cytokines, measured using Luminex XMap technology, and breast cancer phenotypes [ER vs. ER+; triple negative breast cancer (TNBC) vs. luminal A (LumA)]. Ratios of Th1 to Th2 cytokines were also evaluated. Levels of interleukin (IL)-5, a Th-2 cytokine, were higher in ER than in ER+ tumors. The highest tertile of IL-5 was more strongly associated with ER (OR = 2.33, 95 % CI 1.40–3.90) and TNBCs (OR = 2.78, 95 % CI 1.53–5.06) compared to ER+ and LumA cancers, respectively, particularly among premenopausal women (OR = 4.17, 95 % CI 1.86–9.34, ER vs. ER+; OR = 5.60, 95 % CI 2.09–15.01, TNBC vs. LumA). Elevated Th1 cytokines were also detected in women with ER and TNBCs, with women in the highest tertile of interferon α2 (OR = 2.39, 95 % CI 1.31–4.35) or tumor necrosis factor-α (OR = 2.27, 95 % CI 1.21–4.26) being twice as likely to have TNBC versus LumA cancer. When cytokine ratios were examined, women with the highest ratios of Th1 cytokines to IL-5 levels were least likely to have ER or TNBCs compared to ER+ or LumA cancers, respectively. The strongest associations were in premenopausal women, who were up to 80 % less likely to have TNBC than LumA cancers (IL-12p40/IL-5, OR = 0.19, 95 % CI 0.07–0.56). These findings indicate that immune function is associated with ER and TNBC and may be most relevant among younger women, who are likely to be diagnosed with these aggressive phenotypes.


Estrogen negative breast cancer Triple negative breast cancer Cytokines Immune function 



American Joint Committee on Cancer


Breast cancer type 1 susceptibility protein


Chemokine (C–C motif) ligand 2


Chemokine (C–C motif) ligand 7


Chemokine (C–C motif) ligand 11




Chemokine (C–X–C motif) ligand 10


Data Bank and Biorepository


Epidermal growth factor receptor positive


Estrogen receptor


Estrogen receptor positive


Estrogen receptor negative


Granulocyte-colony stimulating factor


Granulocyte macrophage-colony stimulating factor


Human epidermal growth factor receptor 2 negative








Interleukin-1 receptor antagonist


Interferon gamma-induced protein 10


Institutional Review Board


Luminal A


Monocyte chemotactic protein


Macrophage-derived chemokine


Macrophage inflammatory protein-1


Quality control


Roswell Park Cancer Institute


Tumor-associated macrophages


T-helper type 1


T-helper type 2


T-helper type 17


Triple negative breast cancer


Tumor necrosis factor

Supplementary material

10549_2013_2549_MOESM1_ESM.pdf (132 kb)
Table 1Descriptive statistics of 27 cytokines and all ratios examined in 530 women with invasive breast cancer. Specific cutpoints used to define low, medium, and high circulating cytokine levels are provided along with detectable assay limits, interplate coefficient of variations for each cytokine measured, and proportion of samples below the detectable limit. Effect of sample storage and season of blood draw on cytokine levels are also shown. (PDF 133 kb)
10549_2013_2549_MOESM2_ESM.pdf (165 kb)
Table 2Associations between circulating immune markers and risk of ER breast cancer among women with invasive breast cancer (PDF 166 kb)
10549_2013_2549_MOESM3_ESM.pdf (599 kb)
Table 3Associations between circulating immune markers and risk of triple negative versus LumA breast cancer (PDF 599 kb)
10549_2013_2549_MOESM4_ESM.pdf (55 kb)
Table 4Spearman partial correlations between cytokines and/or their ratios significantly associated with ER or TNBCs (PDF 56 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chi-Chen Hong
    • 1
  • Song Yao
    • 1
  • Susan E. McCann
    • 1
  • Ree Y. Dolnick
    • 3
  • Paul K. Wallace
    • 3
  • Zhihong Gong
    • 1
  • Lei Quan
    • 1
  • Kelvin P. Lee
    • 4
  • Sharon S. Evans
    • 4
  • Elizabeth A. Repasky
    • 4
  • Stephen B. Edge
    • 2
  • Christine B. Ambrosone
    • 1
  1. 1.Department of Cancer Prevention and ControlRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of Surgical OncologyRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Department of Flow & Image CytometryRoswell Park Cancer InstituteBuffaloUSA
  4. 4.Department of ImmunologyRoswell Park Cancer InstituteBuffaloUSA

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