Skip to main content

Advertisement

SpringerLink
Log in

The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

Breast cancer is the most prevalent cancer among women worldwide and the fifth cause of death among all cancer patients. Breast cancer development is driven by genetic and epigenetic alterations, with the tumor microenvironment (TME) playing an essential role in disease progression and evolution through mechanisms like inflammation promotion. TNF-α is one of the essential pro-inflammatory cytokines found in the TME of breast cancer patients, being secreted both by stromal cells, mainly by tumor-associated macrophages, and by the cancer cells themselves. In this review, we explore the biological and clinical impact of TNF-α in all stages of breast cancer development. First of all, we explore the correlation between TNF-α expression levels at the tumor site or in plasma/serum of breast cancer patients and their respective clinical status and outcome. Secondly, we emphasize the role of TNF-α signaling in both estrogen-positive and -negative breast cancer cells. Thirdly, we underline TNF-α involvement in epithelial-to-mesenchymal transition (EMT) and metastasis of breast cancer cells, and we point out the contribution of TNF-α to the development of acquired drug resistance.

Conclusions

Collectively, these data reveal a pro-tumorigenic role of TNF-α during breast cancer progression and metastasis. We systemize the knowledge regarding TNF-α-related therapies in breast cancer, and we explain how TNF-α may act as both a target and a drug in different breast cancer therapeutic approaches. By corroborating the known molecular effects of TNF-α signaling in breast cancer cells with the results from several preclinical and clinical trials, including TNF-α-related clinical observations, we conclude that the potential of TNF-α in breast cancer therapy promises to be of great interest.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2018). https://doi.org/10.3322/caac.21492

    Google Scholar 

  2. K.D. Voduc, M.C. Cheang, S. Tyldesley, K. Gelmon, T.O. Nielsen, H. Kennecke, Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 28, 1684–1691 (2010)

    Article  PubMed  Google Scholar 

  3. M.D. Althuis, J.M. Dozier, W.F. Anderson, S.S. Devesa, L.A. Brinton, Global trends in breast cancer incidence and mortality 1973-1997. Int J Epidemiol 34, 405–412 (2005)

    Article  PubMed  Google Scholar 

  4. D. Hanahan, L.M. Coussens, Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012)

    Article  CAS  PubMed  Google Scholar 

  5. Y.A. Fouad, C. Aanei, Revisiting the hallmarks of cancer. Am J Cancer Res 7, 1016–1036 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. N. Eiro, L. Gonzalez, A. Martinez-Ordonez, B. Fernandez-Garcia, L.O. Gonzalez, S. Cid, F. Dominguez, R. Perez-Fernandez, F.J. Vizoso, Cancer-associated fibroblasts affect breast cancer cell gene expression, invasion and angiogenesis. Cell Oncol  41, 369–378 (2018)

    Article  CAS  Google Scholar 

  7. P. Nilendu, S.C. Sarode, D. Jahagirdar, I. Tandon, S. Patil, G.S. Sarode, J.K. Pal, N.K. Sharma, Mutual concessions and compromises between stromal cells and cancer cells: Driving tumor development and drug resistance. Cell Oncol 41, 353–367 (2018)

    Article  CAS  Google Scholar 

  8. F. Chen, X. Zhuang, L. Lin, P. Yu, Y. Wang, Y. Shi, G. Hu, Y. Sun, New horizons in tumor microenvironment biology: Challenges and opportunities. BMC Med 13, 45 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  9. M.R. Junttila, F.J. de Sauvage, Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501, 346–354 (2013)

    Article  CAS  PubMed  Google Scholar 

  10. A.E. Place, S. Jin Huh, K. Polyak, The microenvironment in breast cancer progression: Biology and implications for treatment. Breast Cancer Res 13, 227 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Y. Mao, E.T. Keller, D.H. Garfield, K. Shen, J. Wang, Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32, 303–315 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  12. F.R. Balkwill, M. Capasso, T. Hagemann, The tumor microenvironment at a glance. J Cell Sci 125, 5591–5596 (2012)

    Article  CAS  PubMed  Google Scholar 

  13. D.G. DeNardo, L.M. Coussens, Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression Breast Cancer Res 9, 212 (2007)

    PubMed  Google Scholar 

  14. F. Balkwill, A. Mantovani, Inflammation and cancer: Back to Virchow? Lancet 357, 539–545 (2001)

    Article  CAS  PubMed  Google Scholar 

  15. S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer. Cell 140, 883–899 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. A. Ben-Baruch, Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: Reciprocal tumor-microenvironment interactions. Breast Cancer Res 5, 31–36 (2003)

    Article  CAS  PubMed  Google Scholar 

  17. N. Volodko, A. Reiner, M. Rudas, R. Jakesz, Tumour-associated macrophages in breast cancer and their prognostic correlations. Breast J 7, 6 (1998)

    Google Scholar 

  18. S. Tsutsui, K. Yasuda, K. Suzuki, K. Tahara, H. Higashi, S. Era, Macrophage infiltration and its prognostic implications in breast cancer: The relationship with VEGF expression and microvessel density. Oncol Rep 14, 425–431 (2005)

    CAS  PubMed  Google Scholar 

  19. R.D. Leek, C.E. Lewis, R. Whitehouse, M. Greenall, J. Clarke, A.L. Harris, Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56, 4625–4629 (1996)

    CAS  PubMed  Google Scholar 

  20. E.Y. Lin, J.F. Li, G. Bricard, W. Wang, Y. Deng, R. Sellers, S.A. Porcelli, J.W. Pollard, Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol Oncol 1, 288–302 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  21. K. Galmbacher, M. Heisig, C. Hotz, J. Wischhusen, A. Galmiche, B. Bergmann, I. Gentschev, W. Goebel, U.R. Rapp, J. Fensterle, Shigella mediated depletion of macrophages in a murine breast cancer model is associated with tumor regression. PLoS One 5, e9572 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. S.J. Priceman, J.L. Sung, Z. Shaposhnik, J.B. Burton, A.X. Torres-Collado, D.L. Moughon, M. Johnson, A.J. Lusis, D.A. Cohen, M.L. Iruela-Arispe, L. Wu, Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: Combating tumor evasion of antiangiogenic therapy. Blood 115, 1461–1471 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. E. Azenshtein, G. Luboshits, S. Shina, E. Neumark, D. Shahbazian, M. Weil, N. Wigler, I. Keydar, A. Ben-Baruch, The CC chemokine RANTES in breast carcinoma progression: Regulation of expression and potential mechanisms of promalignant activity. Cancer Res 62, 1093–1102 (2002)

    CAS  PubMed  Google Scholar 

  24. S. Goswami, E. Sahai, J.B. Wyckoff, M. Cammer, D. Cox, F.J. Pixley, E.R. Stanley, J.E. Segall, J.S. Condeelis, Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 65, 5278–5283 (2005)

    Article  CAS  PubMed  Google Scholar 

  25. C. Katanov, S. Lerrer, Y. Liubomirski, L. Leider-Trejo, T. Meshel, J. Bar, R. Feniger-Barish, I. Kamer, G. Soria-Artzi, H. Kahani, D. Banerjee, A. Ben-Baruch, Regulation of the inflammatory profile of stromal cells in human breast cancer: Prominent roles for TNF-alpha and the NF-kappaB pathway. Stem Cell Res Ther 6, 87 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. S.K. Biswas, A. Mantovani, Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat Immunol 11, 889–896 (2010)

    Article  CAS  PubMed  Google Scholar 

  27. A. Salmaninejad, S.F. Valilou, A. Soltani, S. Ahmadi, Y.J. Abarghan, R.J. Rosengren, A. Sahebkar, Tumor-associated macrophages: Role in cancer development and therapeutic implications. Cell Oncol 42, 591–608 (2019)

    Article  Google Scholar 

  28. M. Torroella-Kouri, R. Silvera, D. Rodriguez, R. Caso, A. Shatry, S. Opiela, D. Ilkovitch, R.A. Schwendener, V. Iragavarapu-Charyulu, Y. Cardentey, N. Strbo, D.M. Lopez, Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res 69, 4800–4809 (2009)

    Article  CAS  PubMed  Google Scholar 

  29. D.G. DeNardo, J.B. Barreto, P. Andreu, L. Vasquez, D. Tawfik, N. Kolhatkar, L.M. Coussens, CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. F.O. Martinez, L. Helming, S. Gordon, Alternative activation of macrophages: An immunologic functional perspective. Annu Rev Immunol 27, 451–483 (2009)

    Article  CAS  PubMed  Google Scholar 

  31. S.L. Rego, R.S. Helms, D. Dreau, Tumor necrosis factor-alpha-converting enzyme activities and tumor-associated macrophages in breast cancer. Immunol Res 58, 87–100 (2014)

    Article  CAS  PubMed  Google Scholar 

  32. A.E. Dirkx, M.G. Oude Egbrink, J. Wagstaff, A.W. Griffioen, Monocyte/macrophage infiltration in tumors: Modulators of angiogenesis. J Leukoc Biol 80, 1183–1196 (2006)

    Article  CAS  PubMed  Google Scholar 

  33. C.E. Lewis, J.W. Pollard, Distinct role of macrophages in different tumor microenvironments. Cancer Res 66, 605–612 (2006)

    Article  CAS  PubMed  Google Scholar 

  34. E.Y. Lin, A.V. Nguyen, R.G. Russell, J.W. Pollard, Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193, 727–740 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. F. Balkwill, TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev 25, 409–416 (2006)

    Article  CAS  PubMed  Google Scholar 

  36. F. Yang, Z. Zhao, N. Zhao, Clinical implications of tumor necrosis factor receptor 2 in breast cancer. Oncol Lett 14, 2393–2398 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. E.A. Carswell, L.J. Old, R.L. Kassel, S. Green, N. Fiore, B. Williamson, An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72, 3666–3670 (1975)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. D. Daniel, N.S. Wilson, Tumor necrosis factor: Renaissance as a cancer therapeutic? Curr Cancer Drug Targets 8, 124–131 (2008)

    Article  CAS  PubMed  Google Scholar 

  39. A.L. Seynhaeve, S. Hoving, D. Schipper, C.E. Vermeulen, G. de Wiel-Ambagtsheer, S.T. van Tiel, A.M. Eggermont, T.L. Ten Hagen, Tumor necrosis factor alpha mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response. Cancer Res 67, 9455–9462 (2007)

    Article  CAS  PubMed  Google Scholar 

  40. B.J. Sugarman, B.B. Aggarwal, P.E. Hass, I.S. Figari, M.A. Palladino Jr., H.M. Shepard, Recombinant human tumor necrosis factor-alpha: Effects on proliferation of normal and transformed cells in vitro. Science 230, 943–945 (1985)

    Article  CAS  PubMed  Google Scholar 

  41. F. Balkwill, Tumour necrosis factor and cancer. Nat Rev Cancer 9, 361–371 (2009)

    Article  CAS  PubMed  Google Scholar 

  42. P. Selby, S. Hobbs, C. Viner, E. Jackson, A. Jones, D. Newell, A.H. Calvert, T. McElwain, K. Fearon, J. Humphreys, et al., Tumour necrosis factor in man: Clinical and biological observations. Br J Cancer 56, 803–808 (1987)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. E.T. Creagan, J.S. Kovach, C.G. Moertel, S. Frytak, L.K. Kvols, A phase I clinical trial of recombinant human tumor necrosis factor. Cancer 62, 2467–2471 (1988)

    Article  CAS  PubMed  Google Scholar 

  44. K. Kimura, T. Taguchi, I. Urushizaki, R. Ohno, O. Abe, H. Furue, T. Hattori, H. Ichihashi, K. Inoguchi, H. Majima, et al., Phase I study of recombinant human tumor necrosis factor. Cancer Chemother Pharmacol 20, 223–229 (1987)

    Article  CAS  PubMed  Google Scholar 

  45. M. Blick, S.A. Sherwin, M. Rosenblum, J. Gutterman, Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res 47, 2986–2989 (1987)

    CAS  PubMed  Google Scholar 

  46. S. Gulluoglu, E.C. Tuysuz, M. Sahin, C.K. Yaltirik, A. Kuskucu, F. Ozkan, A.B. Dalan, F. Sahin, U. Ture, O.F. Bayrak, The role of TNF-alpha in chordoma progression and inflammatory pathways. Cell Oncol 42, 663–677 (2019)

  47. G. Sethi, B. Sung, B.B. Aggarwal, TNF: A master switch for inflammation to cancer. Front Biosci 13, 5094–5107 (2008)

    Article  CAS  PubMed  Google Scholar 

  48. J.H. Egberts, V. Cloosters, A. Noack, B. Schniewind, L. Thon, S. Klose, B. Kettler, C. von Forstner, C. Kneitz, J. Tepel, D. Adam, H. Wajant, H. Kalthoff, A. Trauzold, Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 68, 1443–1450 (2008)

    Article  CAS  PubMed  Google Scholar 

  49. G.T. Stathopoulos, A. Kollintza, C. Moschos, I. Psallidas, T.P. Sherrill, E.N. Pitsinos, S. Vassiliou, M. Karatza, S.A. Papiris, D. Graf, D. Orphanidou, R.W. Light, C. Roussos, T.S. Blackwell, I. Kalomenidis, Tumor necrosis factor-alpha promotes malignant pleural effusion. Cancer Res 67, 9825–9834 (2007)

    Article  CAS  PubMed  Google Scholar 

  50. K. Zins, D. Abraham, M. Sioud, S. Aharinejad, Colon cancer cell-derived tumor necrosis factor-alpha mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway. Cancer Res 67, 1038–1045 (2007)

    Article  CAS  PubMed  Google Scholar 

  51. B.B. Aggarwal, Signalling pathways of the TNF superfamily: A double-edged sword. Nat Rev Immunol 3, 745–756 (2003)

    Article  CAS  PubMed  Google Scholar 

  52. D.W. Miles, L.C. Happerfield, M.S. Naylor, L.G. Bobrow, R.D. Rubens, F.R. Balkwill, Expression of tumour necrosis factor (TNF alpha) and its receptors in benign and malignant breast tissue. Int J Cancer 56, 777–782 (1994)

    Article  CAS  PubMed  Google Scholar 

  53. R.D. Leek, R. Landers, S.B. Fox, F. Ng, A.L. Harris, C.E. Lewis, Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br J Cancer 77, 2246–2251 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. G. Soria, M. Ofri-Shahak, I. Haas, N. Yaal-Hahoshen, L. Leider-Trejo, T. Leibovich-Rivkin, P. Weitzenfeld, T. Meshel, E. Shabtai, M. Gutman, A. Ben-Baruch, Inflammatory mediators in breast cancer: Coordinated expression of TNFalpha & IL-1beta with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition. BMC Cancer 11, 130 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. S.M. Sheen-Chen, W.J. Chen, H.L. Eng, F.F. Chou, Serum concentration of tumor necrosis factor in patients with breast cancer. Breast Cancer Res Treat 43, 211–215 (1997)

    Article  CAS  PubMed  Google Scholar 

  56. E.A. Hamed, M.M. Zakhary, D.W. Maximous, Apoptosis, angiogenesis, inflammation, and oxidative stress: Basic interactions in patients with early and metastatic breast cancer. J Cancer Res Clin Oncol 138, 999–1009 (2012)

    Article  CAS  PubMed  Google Scholar 

  57. J.G. Dai, Y.F. Wu, M. Li, Changes of serum tumor markers, immunoglobulins. TNF-α and hsCRP levels in patients with breast cancer and its clinical significance. J Hainan Med Univ 23, 4 (2017)

  58. Y. Ma, Y. Ren, Z.J. Dai, C.J. Wu, Y.H. Ji, J. Xu, IL-6, IL-8 and TNF-alpha levels correlate with disease stage in breast cancer patients. Adv Clin Exp Med 26, 421–426 (2017)

    Article  PubMed  Google Scholar 

  59. H. Bozcuk, G. Uslu, M. Samur, M. Yildiz, T. Ozben, M. Ozdogan, M. Artac, H. Altunbas, I. Akan, B. Savas, Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. Cytokine 27, 58–65 (2004)

    Article  CAS  PubMed  Google Scholar 

  60. G. Tripsianis, E. Papadopoulou, K. Anagnostopoulos, S. Botaitis, M. Katotomichelakis, K. Romanidis, E. Kontomanolis, I. Tentes, A. Kortsaris, Coexpression of IL-6 and TNF-alpha: Prognostic significance on breast cancer outcome. Neoplasma 61, 205–212 (2014)

    Article  CAS  PubMed  Google Scholar 

  61. G. Tripsianis, E. Papadopoulou, K. Romanidis, M. Katotomichelakis, K. Anagnostopoulos, E. Kontomanolis, S. Botaitis, I. Tentes, A. Kortsaris, Overall survival and clinicopathological characteristics of patients with breast cancer in relation to the expression pattern of HER-2, IL-6, TNF-alpha and TGF-beta1. Asian Pac J Cancer Prev 14, 6813–6820 (2013)

    Article  PubMed  Google Scholar 

  62. M.F. Rubio, S. Werbajh, E.G. Cafferata, A. Quaglino, G.P. Colo, I.M. Nojek, E.C. Kordon, V.E. Nahmod, M.A. Costas, TNF-alpha enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene 25, 1367–1377 (2006)

    Article  CAS  PubMed  Google Scholar 

  63. M.A. Rivas, R.P. Carnevale, C.J. Proietti, C. Rosemblit, W. Beguelin, M. Salatino, E.H. Charreau, I. Frahm, S. Sapia, P. Brouckaert, P.V. Elizalde, R. Schillaci, TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK. Akt and NF-kappa B-dependent pathways Exp Cell Res 314, 509–529 (2008)

    CAS  PubMed  Google Scholar 

  64. R. Simstein, M. Burow, A. Parker, C. Weldon, B. Beckman, Apoptosis, chemoresistance, and breast cancer: Insights from the MCF-7 cell model system. Exp Biol Med 228, 995–1003 (2003)

    Article  CAS  PubMed  Google Scholar 

  65. N.J. Donato, J. Klostergaard, Distinct stress and cell destruction pathways are engaged by TNF and ceramide during apoptosis of MCF-7 cells. Exp Cell Res 294, 523–533 (2004)

    Article  CAS  PubMed  Google Scholar 

  66. Y. Wang, X. Wang, H. Zhao, B. Liang, Q. Du, Clusterin confers resistance to TNF-alpha-induced apoptosis in breast cancer cells through NF-kappaB activation and Bcl-2 overexpression. J Chemother 24, 348–357 (2012)

    Article  CAS  PubMed  Google Scholar 

  67. D.I. Jeoung, B. Tang, M. Sonenberg, Effects of tumor necrosis factor-alpha on antimitogenicity and cell cycle-related proteins in MCF-7 cells. J Biol Chem 270, 18367–18373 (1995)

    Article  CAS  PubMed  Google Scholar 

  68. F. Rozen, J. Zhang, M. Pollak, Antiproliferative action of tumor necrosis factor-alpha on MCF-7 breastcancer cells is associated with increased insulin-like growth factor binding protein-3 accumulation. Int J Oncol 13, 865–869 (1998)

    CAS  PubMed  Google Scholar 

  69. C. Luberto, D.F. Hassler, P. Signorelli, Y. Okamoto, H. Sawai, E. Boros, D.J. Hazen-Martin, L.M. Obeid, Y.A. Hannun, G.K. Smith, Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem 277, 41128–41139 (2002)

    Article  CAS  PubMed  Google Scholar 

  70. B.J. Pettus, C.E. Chalfant, Y.A. Hannun, Ceramide in apoptosis: An overview and current perspectives. Biochim Biophys Acta 1585, 114–125 (2002)

    Article  CAS  PubMed  Google Scholar 

  71. X. Cai, C. Cao, J. Li, F. Chen, S. Zhang, B. Liu, W. Zhang, X. Zhang, L. Ye, Inflammatory factor TNF-alpha promotes the growth of breast cancer via the positive feedback loop of TNFR1/NF-kappaB (and/or p38)/p-STAT3/HBXIP/TNFR1. Oncotarget 8, 58338–58352 (2017)

    PubMed  PubMed Central  Google Scholar 

  72. J. Frasor, J.M. Danes, B. Komm, K.C. Chang, C.R. Lyttle, B.S. Katzenellenbogen, Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: Insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144, 4562–4574 (2003)

    Article  CAS  PubMed  Google Scholar 

  73. S.C. Baumgarten, J. Frasor, Minireview: Inflammation: An instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol 26, 360–371 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. J. Frasor, A. Weaver, M. Pradhan, Y. Dai, L.D. Miller, C.Y. Lin, A. Stanculescu, Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res 69, 8918–8925 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. R.H. Straub, The complex role of estrogens in inflammation. Endocr Rev 28, 521–574 (2007)

    Article  CAS  PubMed  Google Scholar 

  76. A. Stanculescu, L.A. Bembinster, K. Borgen, A. Bergamaschi, E. Wiley, J. Frasor, Estrogen promotes breast cancer cell survival in an inhibitor of apoptosis (IAP)-dependent manner. Horm Cancer 1, 127–135 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. M. Kamel, S. Shouman, M. El-Merzebany, G. Kilic, T. Veenstra, M. Saeed, M. Wagih, C. Diaz-Arrastia, D. Patel, S. Salama, Effect of tumour necrosis factor-alpha on estrogen metabolic pathways in breast cancer cells. J Cancer 3, 310–321 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. J. Frasor, A.E. Weaver, M. Pradhan, K. Mehta, Synergistic up-regulation of prostaglandin E synthase expression in breast cancer cells by 17beta-estradiol and proinflammatory cytokines. Endocrinology 149, 6272–6279 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. S.H. Chang, C.H. Liu, R. Conway, D.K. Han, K. Nithipatikom, O.C. Trifan, T.F. Lane, T. Hla, Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci U S A 101, 591–596 (2004)

    Article  CAS  PubMed  Google Scholar 

  80. A.V. Timoshenko, G. Xu, S. Chakrabarti, P.K. Lala, C. Chakraborty, Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res 289, 265–274 (2003)

    Article  CAS  PubMed  Google Scholar 

  81. R.W. Brueggemeier, J.A. Richards, S. Joomprabutra, A.S. Bhat, J.L. Whetstone, Molecular pharmacology of aromatase and its regulation by endogenous and exogenous agents. J Steroid Biochem Mol Biol 79, 75–84 (2001)

    Article  CAS  PubMed  Google Scholar 

  82. Y. Qiao, H. He, P. Jonsson, I. Sinha, C. Zhao, K. Dahlman-Wright, AP-1 is a key regulator of proinflammatory cytokine TNFalpha-mediated triple-negative breast cancer progression. J Biol Chem 291, 18309 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. V. Pileczki, C. Braicu, C.D. Gherman, I. Berindan-Neagoe, TNF-α gene knockout in triple negative breast Cancer cell line induces apoptosis. Int J Mol Sci 14, 9 (2013)

    Google Scholar 

  84. J.F. Bromberg, M.H. Wrzeszczynska, G. Devgan, Y. Zhao, R.G. Pestell, C. Albanese, J.E. Darnell Jr., Stat3 as an oncogene. Cell 98, 295–303 (1999)

    Article  CAS  PubMed  Google Scholar 

  85. F. Liu, X. You, Y. Wang, Q. Liu, Y. Liu, S. Zhang, L. Chen, X. Zhang, L. Ye, The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Carcinogenesis 35, 1144–1153 (2014)

    Article  CAS  PubMed  Google Scholar 

  86. Y. Li, Z. Zhang, X. Zhou, L. Li, Q. Liu, Z. Wang, X. Bai, Y. Zhao, H. Shi, X. Zhang, L. Ye, The oncoprotein HBXIP enhances migration of breast cancer cells through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. Cancer Lett 355, 288–296 (2014)

    Article  CAS  PubMed  Google Scholar 

  87. D.L. Franco, I.M. Nojek, L. Molinero, O.A. Coso, M.A. Costas, Osmotic stress sensitizes naturally resistant cells to TNF-alpha-induced apoptosis. Cell Death Differ 9, 1090–1098 (2002)

    Article  CAS  PubMed  Google Scholar 

  88. B.P. Zhou, M.C. Hu, S.A. Miller, Z. Yu, W. Xia, S.Y. Lin, M.C. Hung, HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. J Biol Chem 275, 8027–8031 (2000)

    Article  CAS  PubMed  Google Scholar 

  89. C.B. Weldon, A.P. Parker, D. Patten, S. Elliott, Y. Tang, D.E. Frigo, C.M. Dugan, E.L. Coakley, N.N. Butler, J.L. Clayton, J. Alam, T.J. Curiel, B.S. Beckman, B.M. Jaffe, M.E. Burow, Sensitization of apoptotically-resistant breast carcinoma cells to TNF and TRAIL by inhibition of p38 mitogen-activated protein kinase signaling. Int J Oncol 24, 1473–1480 (2004)

    CAS  PubMed  Google Scholar 

  90. O.J. Jupp, S.M. McFarlane, H.M. Anderson, A.F. Littlejohn, A.A. Mohamed, R.H. MacKay, P. Vandenabeele, D.J. MacEwan, Type II tumour necrosis factor-alpha receptor (TNFR2) activates c-Jun N-terminal kinase (JNK) but not mitogen-activated protein kinase (MAPK) or p38 MAPK pathways. Biochem J 359, 525–535 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. F. Tang, G. Tang, J. Xiang, Q. Dai, M.R. Rosner, A. Lin, The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol 22, 8571–8579 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Z.G. Liu, H. Hsu, D.V. Goeddel, M. Karin, Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565–576 (1996)

    Article  CAS  PubMed  Google Scholar 

  93. G. Tang, Y. Minemoto, B. Dibling, N.H. Purcell, Z. Li, M. Karin, A. Lin, Inhibition of JNK activation through NF-kappaB target genes. Nature 414, 313–317 (2001)

    Article  CAS  PubMed  Google Scholar 

  94. A. Lin, B. Dibling, The true face of JNK activation in apoptosis. Aging Cell 1, 112–116 (2002)

    Article  CAS  PubMed  Google Scholar 

  95. M.E. Burow, C.B. Weldon, Y. Tang, G.L. Navar, S. Krajewski, J.C. Reed, T.G. Hammond, S. Clejan, B.S. Beckman, Differences in susceptibility to tumor necrosis factor alpha-induced apoptosis among MCF-7 breast cancer cell variants. Cancer Res 58, 4940–4946 (1998)

    CAS  PubMed  Google Scholar 

  96. Y. Wang, B.P. Zhou, Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin J Cancer 30, 8 (2011)

    Google Scholar 

  97. S. Kotiyal, S. Bhattacharya, Breast cancer stem cells. EMT and therapeutic targets Biochem Biophys Res Commun 453, 112–116 (2014)

    Article  CAS  PubMed  Google Scholar 

  98. P. Bhat-Nakshatri, H. Appaiah, C. Ballas, P. Pick-Franke, R. Goulet Jr., S. Badve, E.F. Srour, H. Nakshatri, SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer 10, 411 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. M.K. Asiedu, J.N. Ingle, M.D. Behrens, D.C. Radisky, K.L. Knutson, TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res 71, 4707–4719 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. T. Li, Z. Feng, S. Jia, W. Wang, Z. Du, N. Chen, Z. Chen, Daintain/AIF-1 promotes breast cancer cell migration by up-regulated TNF-alpha via activate p38 MAPK signaling pathway. Breast Cancer Res Treat 131, 891–898 (2012)

    Article  CAS  PubMed  Google Scholar 

  101. C.W. Li, W. Xia, L. Huo, S.O. Lim, Y. Wu, J.L. Hsu, C.H. Chao, H. Yamaguchi, N.K. Yang, Q. Ding, Y. Wang, Y.J. Lai, A.M. LaBaff, T.J. Wu, B.R. Lin, M.H. Yang, G.N. Hortobagyi, M.C. Hung, Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res 72, 1290–1300 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. G. Storci, P. Sansone, S. Mari, G. D'Uva, S. Tavolari, T. Guarnieri, M. Taffurelli, C. Ceccarelli, D. Santini, P. Chieco, K.B. Marcu, M. Bonafe, TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J Cell Physiol 225, 682–691 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Y. Qiao, C.N. Shiue, J. Zhu, T. Zhuang, P. Jonsson, A.P. Wright, C. Zhao, K. Dahlman-Wright, AP-1-mediated chromatin looping regulates ZEB2 transcription: New insights into TNFalpha-induced epithelial-mesenchymal transition in triple-negative breast cancer. Oncotarget 6, 7804–7814 (2015)

    PubMed  PubMed Central  Google Scholar 

  104. M. Yamamoto, Y. Taguchi, T. Ito-Kureha, K. Semba, N. Yamaguchi, J. Inoue, NF-kappaB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype. Nat Commun 4, 2299 (2013)

    Article  PubMed  CAS  Google Scholar 

  105. H. Harrison, G. Farnie, S.J. Howell, R.E. Rock, S. Stylianou, K.R. Brennan, N.J. Bundred, R.B. Clarke, Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 70, 709–718 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. M. Garg, Epithelial-mesenchymal transition - activating transcription factors - multifunctional regulators in cancer. World J Stem Cells 5, 188–195 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  107. Y. Wu, J. Deng, P.G. Rychahou, S. Qiu, B.M. Evers, B.P. Zhou, Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416–428 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. M. Snyder, J. Huang, X.Y. Huang, J.J. Zhang, A signal transducer and activator of transcription 3.Nuclear Factor kappaB (Stat3.NFkappaB) complex is necessary for the expression of fascin in metastatic breast cancer cells in response to interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. J Biol Chem 289, 30082–30089 (2014)

  109. T. Hagemann, J. Wilson, H. Kulbe, N.F. Li, D.A. Leinster, K. Charles, F. Klemm, T. Pukrop, C. Binder, F.R. Balkwill, Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175, 1197–1205 (2005)

    Article  CAS  PubMed  Google Scholar 

  110. D. Wolczyk, M. Zaremba-Czogalla, A. Hryniewicz-Jankowska, R. Tabola, K. Grabowski, A.F. Sikorski, K. Augoff, TNF-alpha promotes breast cancer cell migration and enhances the concentration of membrane-associated proteases in lipid rafts. Cell Oncol 39, 353–363 (2016)

    Article  CAS  Google Scholar 

  111. Y. Yin, X. Chen, Y. Shu, Gene expression of the invasive phenotype of TNF-alpha-treated MCF-7 cells. Biomed Pharmacother 63, 421–428 (2009)

    Article  CAS  PubMed  Google Scholar 

  112. T.H. Lippert, H.J. Ruoff, M. Volm, Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure Arzneimittelforschung 58, 261–264 (2008)

    CAS  PubMed  Google Scholar 

  113. J.M. Roodhart, L.G. Daenen, E.C. Stigter, H.J. Prins, J. Gerrits, J.M. Houthuijzen, M.G. Gerritsen, H.S. Schipper, M.J. Backer, M. van Amersfoort, J.S. Vermaat, P. Moerer, K. Ishihara, E. Kalkhoven, J.H. Beijnen, P.W. Derksen, R.H. Medema, A.C. Martens, A.B. Brenkman, E.E. Voest, Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20, 370–383 (2011)

    Article  CAS  PubMed  Google Scholar 

  114. T. Shree, O.C. Olson, B.T. Elie, J.C. Kester, A.L. Garfall, K. Simpson, K.M. Bell-McGuinn, E.C. Zabor, E. Brogi, J.A. Joyce, Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25, 2465–2479 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. S. Acharyya, T. Oskarsson, S. Vanharanta, S. Malladi, J. Kim, P.G. Morris, K. Manova-Todorova, M. Leversha, N. Hogg, V.E. Seshan, L. Norton, E. Brogi, J. Massague, A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. F. Mosaffa, H. Lage, J.T. Afshari, J. Behravan, Interleukin-1 beta and tumor necrosis factor-alpha increase ABCG2 expression in MCF-7 breast carcinoma cell line and its mitoxantrone-resistant derivative, MCF-7/MX. Inflamm Res 58, 669–676 (2009)

    Article  CAS  PubMed  Google Scholar 

  117. O.M. Malekshah, H. Lage, A.R. Bahrami, J.T. Afshari, J. Behravan, PXR and NF-kappaB correlate with the inducing effects of IL-1beta and TNF-alpha on ABCG2 expression in breast cancer cell lines. Eur J Pharm Sci 47, 474–480 (2012)

    Article  CAS  PubMed  Google Scholar 

  118. M. Maliepaard, M.A. van Gastelen, L.A. de Jong, D. Pluim, R.C. van Waardenburg, M.C. Ruevekamp-Helmers, B.G. Floot, J.H. Schellens, Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 59, 4559–4563 (1999)

    CAS  PubMed  Google Scholar 

  119. K. Miyake, L. Mickley, T. Litman, Z. Zhan, R. Robey, B. Cristensen, M. Brangi, L. Greenberger, M. Dean, T. Fojo, S.E. Bates, Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: Demonstration of homology to ABC transport genes. Cancer Res 59, 8–13 (1999)

    CAS  PubMed  Google Scholar 

  120. Y.H. Kim, G. Ishii, K. Goto, S. Ota, K. Kubota, Y. Murata, M. Mishima, N. Saijo, Y. Nishiwaki, A. Ochiai, Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer. Lung Cancer 65, 105–111 (2009)

    Article  PubMed  Google Scholar 

  121. D. Steinbach, W. Sell, A. Voigt, J. Hermann, F. Zintl, A. Sauerbrey, BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia 16, 1443–1447 (2002)

    Article  CAS  PubMed  Google Scholar 

  122. M. Pradhan, L.A. Bembinster, S.C. Baumgarten, J. Frasor, Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements. J Biol Chem 285, 31100–31106 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. P. Feliciano, CXCL1 and CXCL2 link metastasis and chemoresistance. Nat Genet 44, 8 (2012)

    Google Scholar 

  124. N.J. Roberts, S. Zhou, L.A. Diaz Jr., M. Holdhoff, Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2, 739–751 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  125. H.J. Meany, N.L. Seibel, J. Sun, J.Z. Finklestein, J. Sato, J. Kelleher, P. Sondel, G. Reaman, Phase 2 trial of recombinant tumor necrosis factor-alpha in combination with dactinomycin in children with recurrent Wilms tumor. J Immunother 31, 679–683 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. V. Gregorc, A. Santoro, E. Bennicelli, C.J. Punt, G. Citterio, J.N. Timmer-Bonte, F. Caligaris Cappio, A. Lambiase, C. Bordignon, C.M. van Herpen, Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours. Br J Cancer 101, 219–224 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. T. Fukushima, M. Yamamoto, S. Oshiro, H. Tsugu, K. Hirakawa, G. Soma, Recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2) immunotherapy with ranimustine chemotherapy and concurrent radiation therapy for malignant astrocytomas. Anticancer Res 23, 4473–4481 (2003)

    CAS  PubMed  Google Scholar 

  128. J.H. Schiller, P.L. Witt, B. Storer, D. Alberti, M.B. Tombes, R. Arzoomanian, R.R. Brown, R.A. Proctor, S.D. Voss, D.R. Spriggs, et al., Clinical and biologic effects of combination therapy with gamma-interferon and tumor necrosis factor. Cancer 69, 562–571 (1992)

    Article  CAS  PubMed  Google Scholar 

  129. J.H. Schiller, C. Morgan-Ihrig, M.L. Levitt, Concomitant administration of interleukin-2 plus tumor necrosis factor in advanced non-small cell lung cancer. Am J Clinic Oncol 18, 47–51 (1995)

    Article  CAS  Google Scholar 

  130. K. Greish, S. Taurin, M.A. Morsy, The effect of adjuvant therapy with TNF-alpha on animal model of triple-negative breast cancer. Ther Deliv 9, 333–342 (2018)

    Article  CAS  PubMed  Google Scholar 

  131. X. Wu, M.Y. Wu, M. Jiang, Q. Zhi, X. Bian, M.D. Xu, F.R. Gong, J. Hou, M. Tao, L.M. Shou, W. Duan, K. Chen, M. Shen, W. Li, TNF-alpha sensitizes chemotherapy and radiotherapy against breast cancer cells. Cancer Cell Int 17, 13 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. A. Sacchi, A. Gasparri, C. Gallo-Stampino, S. Toma, F. Curnis, A. Corti, Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha. Clin Cancer Res 12, 175–182 (2006)

    Article  CAS  PubMed  Google Scholar 

  133. G.F. Paciotti, L. Myer, D. Weinreich, D. Goia, N. Pavel, R.E. McLaughlin, L. Tamarkin, Colloidal gold: A novel nanoparticle vector for tumor directed drug delivery. Drug Deliv 11, 169–183 (2004)

    Article  CAS  PubMed  Google Scholar 

  134. N.A. Koonce, C.M. Quick, M.E. Hardee, A. Jamshidi-Parsian, J.A. Dent, G.F. Paciotti, D. Nedosekin, R.P. Dings, R.J. Griffin, Combination of gold nanoparticle-conjugated tumor necrosis factor-alpha and radiation therapy results in a synergistic antitumor response in murine carcinoma models. Int J Radiat Oncol Biol Phys 93, 588–596 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  135. S.K. Libutti, G.F. Paciotti, A.A. Byrnes, H.R. Alexander Jr., W.E. Gannon, M. Walker, G.D. Seidel, N. Yuldasheva, L. Tamarkin, Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin Cancer Res 16, 6139–6149 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. T. Hamaguchi, H. Wakabayashi, A. Matsumine, A. Sudo, A. Uchida, TNF inhibitor suppresses bone metastasis in a breast cancer cell line. Biochem Biophys Res Commun 407, 525–530 (2011)

    Article  CAS  PubMed  Google Scholar 

  137. M. Yu, X. Zhou, L. Niu, G. Lin, J. Huang, W. Zhou, H. Gan, J. Wang, X. Jiang, B. Yin, Z. Li, Targeting transmembrane TNF-alpha suppresses breast cancer growth. Cancer Res 73, 4061–4074 (2013)

    Article  CAS  PubMed  Google Scholar 

  138. X. Ji, Z. Peng, X. Li, Z. Yan, Y. Yang, Z. Qiao, Y. Liu, Neutralization of TNFalpha in tumor with a novel nanobody potentiates paclitaxel-therapy and inhibits metastasis in breast cancer. Cancer Lett 386, 24–34 (2017)

    Article  CAS  PubMed  Google Scholar 

  139. S. Madhusudan, M. Foster, S.R. Muthuramalingam, J.P. Braybrooke, S. Wilner, K. Kaur, C. Han, S. Hoare, F. Balkwill, D.C. Talbot, T.S. Ganesan, A.L. Harris, A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res 10, 6528–6534 (2004)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Competitiveness Operational Programme 2014-2020, Contract no. 41/ 02.09.2016, MySMIS 103557, Project title: Genomic and microfluidic approaches towards blocking breast cancer cell invasion and metastasis – BREASTMINCROGENOMICS. The authors thank to Mihail Buse for proofreading and editing the English language.

Author information

Authors and Affiliations

  1. Department of Functional Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca, Romania

    Daniel Cruceriu, Oana Baldasici, Ovidiu Balacescu & Ioana Berindan-Neagoe

  2. Department of Molecular Biology and Biotechnology, “Babes-Bolyai” University, Cluj-Napoca, Romania

    Daniel Cruceriu

  3. 11th Department of Medical Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 34-36 Republicii Street, 400015, Cluj-Napoca, Romania

    Ovidiu Balacescu

  4. Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  5. MedFuture Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 23 Marinescu Street, 400337, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

Authors
  1. Daniel Cruceriu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oana Baldasici
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ovidiu Balacescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ioana Berindan-Neagoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ovidiu Balacescu or Ioana Berindan-Neagoe.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cruceriu, D., Baldasici, O., Balacescu, O. et al. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches. Cell Oncol. 43, 1–18 (2020). https://doi.org/10.1007/s13402-019-00489-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-019-00489-1

Keywords

Search

Navigation