Tumor Biology

, Volume 37, Issue 3, pp 3775–3783 | Cite as

Early downregulation of acute phase proteins after doxorubicin exposition in patients with breast cancer

  • Carolina PanisEmail author
  • Luciana Pizzatti
  • Aedra Carla Bufalo
  • Ana Cristina Herrera
  • Vanessa Jacob Victorino
  • Rubens Cecchini
  • Eliana Abdelhay
Original Article


Chemotherapy remains the first-choice option for adjuvant therapy in breast cancer. Here, we investigated the impact of the first chemotherapic cycle of doxorubicin on the plasmatic–proteomic profiling of women diagnosed with breast cancer (n = 87). Blood samples were obtained from the same patient before and after doxorubicin infusion (1 h, 60 mg/m2) and processed for label-free LC-MS proteomic screening. A total of 80 proteins were downregulated after chemotherapy. In silico analysis revealed that the main biological process enrolled was inflammation and canonical pathways involving acute phase proteins. TNF-α, IL-1β, IL-12, TGF-β1, clusterin, and gelsolin were chosen as relevant for further validation. All selected targets presented reduced plasmatic levels after treatment. Our results indicate that doxorubicin downregulated acute phase proteins immediately after its infusion. Since such proteins are cancer promoting, its downregulation could support the effectiveness of doxorubicin along treatment.


Breast cancer Doxorubicin Label-free proteomics Cytokines Acute phase proteins Downregulation 



The authors are grateful to the Conselho Nacional de Desenvolvimento Tecnológico (CNPq), INCT para o Controle do Câncer and Fundação Araucária for providing the financial support of the study.

Compliance with ethical standards

Conflict of interest


Supplementary material

13277_2015_4203_MOESM1_ESM.xls (40 kb)
Supplementary Table 1 (XLS 40kb)
13277_2015_4203_MOESM2_ESM.xls (1.8 mb)
Supplementary Table 2 (XLS 1841kb)
13277_2015_4203_MOESM3_ESM.xls (1.9 mb)
Supplementary Table 3 (XLS 1981kb)
13277_2015_4203_MOESM4_ESM.xls (58 kb)
Supplementary Table 4 (XLS 58kb)
13277_2015_4203_MOESM5_ESM.xls (58 kb)
Supplementary Table 5 (XLS 57kb)


  1. 1.
    Cecilio AP, Takakura ET, Jumes JJ, Dos Santos JW, Herrera AC, Victorino VJ, et al. Breast cancer in Brazil: epidemiology and treatment challenges. Breast Cancer. 2015;7:43–9.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Chew E. Adjuvant therapy for breast cancer - who should get what? West J Med. 2001;174(4):284–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Prietsman TJ. Results of a prospective clinical trial comparing two cytotoxic regimes containing adriamycin in women with advanced breast cancer. Clin Oncol. 1975;1(3):207–11.Google Scholar
  4. 4.
    Sparano JA, Makhson AN, Semiglazov VF, Tjulandin SA, Balashova OI, Bondarenko IN, et al. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel Monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol. 2009;20(27):4522–9.CrossRefGoogle Scholar
  5. 5.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56(2):185–229.CrossRefPubMedGoogle Scholar
  6. 6.
    Kim ES, Cha Y, Ham M, Jung J, Kim SG, Hwang S, et al. Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPβ and potentiates breast cancer progression. Oncogene. 2014;33(27):3583–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Ham M, Moon A. Inflammatory and microenvironmental factors involved in breast cancer progression. Arch Pharm Res. 2013;36(12):1419–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Lakota K, Zigon P, Mrak-Poljsak K, Rozman B, Shoenfeld Y, Sodin-Semrl S. Antibodies against acute phase proteins and their functions in the pathogenesis of disease: a collective profile of 25 different antibodies. Autoimmun Rev. 2011;10(12):779–89.CrossRefPubMedGoogle Scholar
  9. 9.
    Pensa S, Watson CJ, Poli V. Stat3 and the inflammation/acute phase response in involution and breast cancer. J Mammary Gland Biol Neoplasia. 2009;14(2):121–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Tisdale MJ. Pathogenesis of cancer cachexia. J Support Oncol. 2003;1(3):159–68.PubMedGoogle Scholar
  11. 11.
    Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke SL, Robinson AP. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool? J Transl Med. 2009;7:102.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ansar W, Ghosh S. C-reactive protein and the biology of disease. Immunol Res. 2013;56(1):131–42.CrossRefPubMedGoogle Scholar
  13. 13.
    Noguchi Y, Yoshikawa T, Matsumoto A, Svaninger G, Gelin J. Are cytokines possible mediators of cancer cachexia? Surg Today. 1996;26(7):467–75.CrossRefPubMedGoogle Scholar
  14. 14.
    Stephens NA, Skipworth RJ, Fearon KC. Cachexia, survival and the acute phase response. Curr Opin Support Palliat Care. 2008;2(4):267–74.CrossRefPubMedGoogle Scholar
  15. 15.
    Michlmayr A, Bachleitner-Hofmann T, Baumann S, Marchetti-Deschmann M, Rech-Weichselbraun I, Burghuber C, et al. Modulation of plasma complement by the initial dose of epirubicin/docetaxel therapy in breast cancer and its predictive value. Br J Cancer. 2010;103(8):1201–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Panis C, Pizzatti L, Herrera AC, Cecchini R, Abdelhay E. Putative circulating markers of the early and advanced stages of breast cancer identified by high-resolution label-free proteomics. Cancer Lett. 2013;330(1):57–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Panis C, Pizzatti L, Herrera AC, Corrêa S, Binato R, Abdelhay E. Label-free proteomic analysis of breast cancer molecular subtypes. J Proteome Res. 2014;13(11):4752–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Panis C, Pizzatti L, Corrêa S, Binato R, Lemos GF, Herrera AC, et al. The positive is inside the negative: HER2-negative tumors can express the HER2 intracellular domain and present a HER2-positive phenotype. Cancer Lett. 2015;357(1):186–95.CrossRefPubMedGoogle Scholar
  19. 19.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Urol. 2005;2(8):416–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Panis C, Pizzatti L, Abdelhay E. How can proteomics reach cancer biomarkers? Curr Proteomics. 2013;10(2):136–49.CrossRefGoogle Scholar
  21. 21.
    Pizzatti L, Panis C, Lemos G, Rocha M, Cecchini R, Souza GH, et al. Label-free MSE proteomic analysis of chronic myeloid leukemia bone marrow plasma: disclosing new insights from therapy resistance. Proteomics. 2012;12(17):2618–31.CrossRefPubMedGoogle Scholar
  22. 22.
    Chen ST, Pan TL, Tsai YC, Huang CM. Proteomics reveals protein profile changes in doxorubicin--treated MCF-7 human breast cancer cells. Cancer Lett. 2002;181(1):95–107.CrossRefPubMedGoogle Scholar
  23. 23.
    Kumar SN, Konorev EA, Aggarwal D, Kalyanaraman B. Analysis of proteome changes in doxorubicin-treated adult rat cardiomyocyte. J Proteomics. 2011;74(5):683–97.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lee SH, Kim SY, Kim JH, Jung HY, Moon JH, Bae KH, et al. Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model. Mol Med Rep. 2012;6(1):157–62.PubMedGoogle Scholar
  25. 25.
    Panis C. Unraveling oxidation-induced modifications in proteins by proteomics. Adv Protein Chem Struct Biol. 2014;94:19–38.CrossRefPubMedGoogle Scholar
  26. 26.
    Kono H, Onda A, Yanagida T. Molecular determinants of sterile inflammation. Curr Opin Immunol. 2014;26:147–56.CrossRefPubMedGoogle Scholar
  27. 27.
    Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122(4):143–59.CrossRefGoogle Scholar
  28. 28.
    Desborough JP. The stress response to trauma and surgery. Br J Anaesth. 2000;85(1):109–17.CrossRefPubMedGoogle Scholar
  29. 29.
    Panis C, Victorino VJ, Herrera AC, Freitas LF, De Rossi T, Campos FC, et al. Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer. Breast Cancer Res Treat. 2012;133(3):881–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer. 2014;14(11):754–62.CrossRefPubMedGoogle Scholar
  31. 31.
    Hamaguchi T, Wakabayashi H, Matsumine A, Sudo A, Uchida A. TNF inhibitor suppresses bone metastasis in a breast cancer cell line. Biochem Biophys Res Commun. 2011;407(3):525–30.CrossRefPubMedGoogle Scholar
  32. 32.
    Yu M, Zhou X, Niu L, Lin G, Huang J, Zhou W, et al. Targeting transmembrane TNF-α suppresses breast cancer growth. Cancer Res. 2013;73(13):4061–74.CrossRefPubMedGoogle Scholar
  33. 33.
    Fruehauf JP, Sinha BK. Selective formation of tumor necrosis factor-alpha (TNF) degradation products contributes to TNF mediated cytotoxicity. Oncol Res. 1992;4(3):91–101.PubMedGoogle Scholar
  34. 34.
    Suswam EA, Nabors LB, Huang Y, Yang X, King PH. IL-1beta induces stabilization of IL-8 mRNA in malignant breast cancer cells via the 3′ untranslated region: involvement of divergent RNA-binding factors HuR, KSRP and TIAR. Int J Cancer. 2005;113(6):911–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Schwartz Y, Avraham R, Benish M, Rosenne E, Ben-Eliyahu S. Prophylactic IL-12 treatment reduces postoperative metastasis: mediation by increased numbers but not cytotoxicity of NK cells. Breast Cancer Res Treat. 2008;107(2):211–23.CrossRefPubMedGoogle Scholar
  36. 36.
    Derynck R, Muthusamy BP, Saeteurn KY. Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition. Curr Opin Cell Biol. 2014;31:56–66.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zarzynska JM. Two faces of TGF-beta1 in breast cancer. Mediat Inflamm. 2014;2014:141747.CrossRefGoogle Scholar
  38. 38.
    Falgarone G, Chiocchia G. Chapter 8: clusterin: a multifacet protein at the crossroad of inflammation and autoimmunity. Adv Cancer Res. 2009;104:139–70.CrossRefPubMedGoogle Scholar
  39. 39.
    Djeu JY, Wei S. Clusterin and chemoresistance. Adv Cancer Res. 2009;105:77–92.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Niu ZH, Wang Y, Chun B, Li CX, Wu L. Secretory clusterin (sCLU) overexpression is associated with resistance to preoperative neoadjuvant chemotherapy in primary breast cancer. Eur Rev Med Pharmacol Sci. 2013;17(10):1337–44.PubMedGoogle Scholar
  41. 41.
    Li GH, Arora PD, Chen Y, McCulloch CA, Liu P. Multifunctional roles of gelsolin in health and diseases. Med Res Rev. 2012;32(5):999–1025.CrossRefPubMedGoogle Scholar
  42. 42.
    Van den Abbeele A, De Corte V, Van Impe K, Bruyneel E, Boucherie C, Bracke M, et al. Downregulation of gelsolin family proteins counteracts cancer cell invasion in vitro. Cancer Lett. 2007;255(1):57–70.CrossRefPubMedGoogle Scholar
  43. 43.
    Buranrat B, Connor JR. Cytoprotective effects of ferritin on doxorubicin-induced breast cancer cell death. Oncol Rep. 2015. doi: 10.3892/or.2015.4250.PubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Carolina Panis
    • 1
    • 2
    Email author
  • Luciana Pizzatti
    • 1
    • 3
  • Aedra Carla Bufalo
    • 2
  • Ana Cristina Herrera
    • 4
  • Vanessa Jacob Victorino
    • 2
    • 5
  • Rubens Cecchini
    • 6
  • Eliana Abdelhay
    • 1
    • 7
  1. 1.Laboratório de Células TroncoInstituto Nacional do Câncer, INCARio de JaneiroBrazil
  2. 2.Laboratório de Mediadores InflamatóriosUniversidade Estadual do Oeste do Paraná, UNIOESTEFrancisco BeltrãoBrazil
  3. 3.Departamento de Bioquímica, Instituto de QuímicaUniversidade Federal do Rio de Janeiro, UFRJRio de JaneiroBrazil
  4. 4.Pontifícia Universidade Católica, PUCLondrinaBrazil
  5. 5.Faculdade de MedicinaUniversidade de São Paulo, USPSão PauloBrazil
  6. 6.Laboratório de Fisiopatologia de Radicais LivresUniversidade Estadual de LondrinaLondrinaBrazil
  7. 7.INCT para o Controle do CâncerRio de JaneiroBrazil

Personalised recommendations