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Pro-inflammatory cytokines and growth factors in human milk: an exploratory analysis of racial differences to inform breast cancer etiology

Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

Analysis of cytokines and growth factors in human milk offers a noninvasive approach for studying the microenvironment of the postpartum breast, which may better reflect tissue levels than testing blood samples. Given that Black women have a higher incidence of early-onset breast cancers than White women, we hypothesized that milk of the former contains higher levels of pro-inflammatory cytokines, adipokines, and growth factors.

Methods

Participants included 130 Black and 162 White women without a history of a breast biopsy who completed a health assessment questionnaire and donated milk for research. Concentrations of 15 analytes in milk were examined using two multiplex and 4 single-analyte electrochemiluminescent sandwich assays to measure pro-inflammatory cytokines, angiogenesis factors, and adipokines. Mixed-effects ordinal logistic regression was used to identify determinants of analyte levels and to compare results by race, with adjustment for confounders. Factor analysis was used to examine covariation among analytes.

Results

Thirteen of 15 analytes were detected in ≥ 25% of the human milk specimens. In multivariable models, elevated BMI was significantly associated with increased concentrations of 5 cytokines: IL-1β, bFGF, FASL, EGF, and leptin (all p-trend < 0.05). Black women had significantly higher levels of leptin and IL-1β, controlling for BMI. Factor analysis of analyte levels identified two factors related to inflammation and growth factor pathways.

Conclusion

This exploratory study demonstrated the feasibility of measuring pro-inflammatory cytokines, adipokines, and angiogenesis factors in human milk, and revealed higher levels of some pro-inflammatory factors, as well as increased leptin levels, among Black as compared with White women.

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References

  1. Anderson KN, Schwab RB, Martinez ME (2014) Reproductive risk factors and breast cancer subtypes: a review of the literature. Breast Cancer Res Treat 144(1):1–10. https://doi.org/10.1007/s10549-014-2852-7

    Article  PubMed  PubMed Central  Google Scholar 

  2. Holm J, Eriksson L, Ploner A et al (2017) Assessment of breast cancer risk factors reveals subtype heterogeneity. Can Res 2017 Jul 1;77(13):3708–3717. https://doi.org/10.1158/0008-5472.CAN-16-2574

    Article  CAS  Google Scholar 

  3. Palmer JR, Viscidi E, Troester MA et al (2014) Parity, lactation and breast cancer subtypes in African American women: results from the AMBER consortium. J Natl Cancer Inst 106(10):1–8. https://doi.org/10.1093/jnci/dju237

    Article  CAS  Google Scholar 

  4. Victora CG, Bahl R, Barros AJD et al (2016) Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 387:475–490. https://doi.org/10.1016/S0140-6736(15)01024-7

    Article  PubMed  Google Scholar 

  5. DeSantis C, Ma J, Sauer AG et al. (2017) Breast Cancer Statistics, Racial Disparity in Mortality by State. CA Cancer J Clin. https://doi.org/10.3322/caac.2141

  6. Pierobon M, Frankenfeld CL (2013 Jan) Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat 137(1):307–314. https://doi.org/10.1007/s10549-012-2339-3

    Article  PubMed  Google Scholar 

  7. Hawkes JS, Bryan DL, Gibson RA (2002) Cytokine production by human milk cells and peripheral blood mononuclear cells from the same mothers. J Clin Immunol 22(6):338–344

    Article  CAS  Google Scholar 

  8. Hines EP, Rayner JL, Barbee R, Moreland RA, Valcour A, Schmid JE, Fenton SE (2007) Assays for endogenous components of human milk: comparison of fresh and frozen samples and corresponding analytes in serum. J Hum Lact 23(2):144–156. https://doi.org/10.1177/0890334407300334

    Article  PubMed  Google Scholar 

  9. Ozarda Y, Gunes Y, Tuncer GO (2012) The concentration of adiponectin in breast milk is related to maternal hormonal and inflammatory status during 6 months of lactation. Clin Chem Lab Med 50(5):911–917. https://doi.org/10.1515/cclm-2011-0724

    Article  CAS  PubMed  Google Scholar 

  10. Arcaro KF, Browne EP, Qin W et al (2012) Differential expression of cancer-related proteins in paired breastmilk samples from women with breast cancer. J Hum Lact 28:543–547. https://doi.org/10.1177/0890334412453205

    Article  PubMed  Google Scholar 

  11. Qin W, Zhang K, Kliethermes B et al. Differential expression of cancer associated proteins in breastmilk based on age at first full term pregnancy. BMC Cancer. 2012 Mar 21;12:100. https://doi.org/10.1186/1471-2407-12-100

  12. Yang HP, Schneider SS, Chisholm CM et al. (2015) Association of TGF-β2 levels in breastmilk with severity of breast biopsy diagnosis. Cancer Causes Control 26(3):345–354. https://doi.org/10.1007/s10552-014-0498-8

    Article  PubMed  PubMed Central  Google Scholar 

  13. Murphy J, Sherman ME, Browne EP et al (2016 May) Potential of breastmilk analysis to inform early events in breast carcinogenesis: rationale and considerations. Breast Cancer Res Treat 157(1):13–22. https://doi.org/10.1007/s10549-016-3796-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wong CM, Anderton DL, Smith-Schneider S, Wing MA, Griven MC, Arcaro K. Quantitative analysis of promoter methylation in exfoliated epithelial cells isolated from breast milk of healthy women. Epigenetics. 2010 Oct 1;5(7):645–655. https://doi.org/10.4161/epi.5.7.1296

  15. Browne EP, Punska EC, Lenington S, Otis CN, Anderton DL, Arcaro KF (2011) Increased promoter methylation in exfoliated breast epithelial cells in women with a previous breast biopsy. Epigenetics 6:1425–1435. https://doi.org/10.4161/epi.6.12.18280

    Article  CAS  PubMed  Google Scholar 

  16. Andreas NJ, Hyde MJ, Gale C et al (2014) Effect of maternal body mass index on hormones in breast milk: a systematic review. PloS ONE 9(12):e11. https://doi.org/10.1371/journal.pone.0115043

    Article  CAS  Google Scholar 

  17. Savino F, Sardo A, Rossi L, Benetti S, Savino A, Silvestro L. Mother and infant body mass index, breast milk leptin and their serum leptin values. Nutrients 2016;8(6). https://doi.org/10.3390/nu8060383

    Article  Google Scholar 

  18. Weyermann M, Beermann C, Brenner H, Rothenbacher D (2006) Adiponectin and leptin in maternal serum, cord blood,and breast milk. Clin Chem 52(11):2095–2102. https://doi.org/10.1373/clinchem.2006.071019

    Article  CAS  PubMed  Google Scholar 

  19. Andreas NJ, Hyde MJ, Herbert BR et al (2016) Impact of maternal BMI and sampling strategy on the concentration of leptin, insulin, ghrelin and resistin in breast milk across a single feed: a longitudinal cohort study. BMJ Open 6(7):e010778. https://doi.org/10.1136/bmjopen-2015-010778

    Article  PubMed  PubMed Central  Google Scholar 

  20. Agarwal S, Karmaus W, Davis S, Gangur V (2011) Immune markers in breast milk and fetal and maternal body fluids: a systematic review of perinatal concentrations. J Hum Lactation 27(2):171–186. https://doi.org/10.1177/0890334410395761

    Article  Google Scholar 

  21. Cohen SS, Fowke JH, Cai Q et al (2012) Differences in the association between serum leptin levels and body mass index in black and white women: a report from the Southern Community Cohort Study. Ann Nutr Metab 60(2):90–97

    Article  CAS  Google Scholar 

  22. Azrad M, Gower BA, Hunter GR et al (2013) Racial differences in adiponectin and leptin in healthy premenopausal women. Endocrine 43:586. https://doi.org/10.1007/s12020-012-9797-6

    Article  CAS  PubMed  Google Scholar 

  23. Barone I, Giordano C, Bonofiglio D, Andò S, Catalano S (2016) Leptin, obesity and breast cancer: progress to understanding the molecular connections. Curr Opin Pharmacol 31;83–89. https://doi.org/10.1016/j.coph.2016.10.003

    Article  CAS  PubMed  Google Scholar 

  24. Matthews SB, Thompson HJ (2016) The Obesity-breast cancer conundrum: an analysis of the issues. Int J Mol Sci; 17(6):989. https://doi.org/10.3390/ijms17060989

    Article  CAS  PubMed Central  Google Scholar 

  25. Harris HR, Tworoger Shelley S, Hankinson SE, Rosner BA, Michels KB (2011) Plasma leptin levels and risk of breast cancer in premenopausal women. Cancer Prev Res (Philadelphia Pa) 4(9):1449–1456. https://doi.org/10.1158/1940-6207.CAPR-11-0125

    Article  CAS  Google Scholar 

  26. Young B, Patinkin Z, Palmer C, de La Houssaye B, Barbour LA, Hernandez T, Friedman J, Krebs NF (2017) Human milk insulin is related to maternal plasma insulin and BMI - But other components of human milk do not differ by BMI. Eur J Clin Nutr 71(9):1094–1100. https://doi.org/10.1038/ejcn.2017.75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Voronov E, Dotan S, Krelin Y, Song X, Elkabets M, Carmi Y, Rider P, Cohen I, Romzova M, Kaplanov I, Apte R (2013) Unique versus redundant functions of IL-1α and IL-1β in the tumor microenvironment. Front Immunol 4:177. https://doi.org/10.3389/fimmu.2013.00177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Burch J, Karmaus W, Gangur V, Soto-Ramírez N, Yousefi M, Goetzl LM (2013) Pre- and perinatal characteristics and breast milk immune markers. Pediatr Res 74(5):615–621. https://doi.org/10.1038/pr.2013.141

    Article  CAS  PubMed  Google Scholar 

  29. Fornetti J, Martinson HA, Betts CB et al (2014) Mammary gland involution as an immunotherapeutic target for postpartum breast cancer. J Mammary Gland Biol Neoplasia 2:213–228. https://doi.org/10.1007/s10911-014-9322-z

    Article  Google Scholar 

  30. Faupel-Badger JM, Arcaro KF, Balkam JJ et al (2013) Postpartum remodeling, lactation, and breast cancer risk: summary of a National Cancer Institute-sponsored workshop. J Natl Cancer Inst 105(3):166–174. https://doi.org/10.1093/jnci/djs505

    Article  PubMed  Google Scholar 

  31. Lyons TR, O’Brien J, Borges VF et al (2011) Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17(9):1109–1115

    Article  CAS  Google Scholar 

  32. Lawrence RA (1999) Storage of human milk and the influence of procedures on immunological components of human milk. Acta Paediatr Suppl 88(430):14–18

    Article  CAS  Google Scholar 

  33. Chang JC, Chen CH, Fang LJ, Tsai CR, Chang YC, Wang TM (2013) Influence of prolonged storage process, pasteurization, and heat treatment on biologically-active human milk proteins. Pediatr Neonatol 54(6):360–366. https://doi.org/10.1016/j.pedneo.2013.03.018

    Article  PubMed  Google Scholar 

  34. Chollet-Hinton LS, Stuebe AM, Casbas-Hernandez P, Chetwynd E, Troester MA (2014) Temporal trends in the inflammatory cytokine profile of human breastmilk. Breastfeed Med 9(10):530–537. https://doi.org/10.1089/bfm.2014.0043

    Article  PubMed  PubMed Central  Google Scholar 

  35. Collado MC, Santaella M, Mira-Pascual L, Martínez-Arias E, Khodayar-Pardo P, Ros G, Martínez-Costa C. Longitudinal study of cytokine expression, lipid profile and neuronal growth factors in human breast milk from term and preterm deliveries. Nutrients. 2015 Oct 19;7(10):8577–8591. https://doi.org/10.3390/nu7105415

    Article  Google Scholar 

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Acknowledgements

Funding was provided by National Cancer Institute (Bench to Bedside Award) to authors Mark E. Sherman, Kathleen F. Arcaro, and Gretchen L. Gierach.

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Correspondence to Jeanne Murphy.

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Gretchen L. Gierach, Kathleen F. Arcaro, Mark E. Sherman—Co-senior authors.

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Murphy, J., Pfeiffer, R.M., Lynn, B.C.D. et al. Pro-inflammatory cytokines and growth factors in human milk: an exploratory analysis of racial differences to inform breast cancer etiology. Breast Cancer Res Treat 172, 209–219 (2018). https://doi.org/10.1007/s10549-018-4907-7

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  • DOI: https://doi.org/10.1007/s10549-018-4907-7

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