Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Inflammatory breast cancer biology: the tumour microenvironment is key

Nature Reviews Cancer volume 18, pages 485–499 (2018)Cite this article

Subjects

An Author Correction to this article was published on 10 May 2018

This article has been updated

Abstract

Inflammatory breast cancer (IBC) is a rare and aggressive disease that accounts for ~2–4% of all breast cancers. However, despite its low incidence rate, IBC is responsible for 7–10% of breast cancer-related mortality in Western countries. Thus, the discovery of robust biological targets and the development of more effective therapeutics in IBC are crucial. Despite major international efforts to understand IBC biology, genomic studies have not led to the discovery of distinct biological mechanisms in IBC that can be translated into novel therapeutic strategies. In this Review, we discuss these molecular profiling efforts and highlight other important aspects of IBC biology. We present the intrinsic characteristics of IBC, including stemness, metastatic potential and hormone receptor positivity; the extrinsic features of the IBC tumour microenvironment (TME), including various constituent cell types; and lastly, the communication between these intrinsic and extrinsic components. We summarize the latest perspectives on the key biological features of IBC, with particular emphasis on the TME as an important contributor to the aggressive nature of IBC. On the basis of the current understanding of IBC, we hope to develop the next generation of translational studies, which will lead to much-needed survival improvements in patients with this deadly disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of intrinsic characteristics of IBC cells and tumour emboli.
Fig. 2: Intrinsic and extrinsic contributors to the aggressive nature of IBC.

Similar content being viewed by others

Change history

  • 10 May 2018

    The originally published article contained an error in Table 1, in which two neoadjuvant clinical trials (NCT02876107 and NCT03101748) were not included. This omission has been corrected in the online and print versions of the manuscript through the addition of these two trials and their relevant details (agents, cohort details, targeted biology, main targeted pathway or characteristic and phase) to Table 1.

References

  1. Chang, S., Parker, S. L., Pham, T., Buzdar, A. U. & Hursting, S. D. Inflammatory breast carcinoma incidence and survival: the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, 1975–1992. Cancer 82, 2366–2372 (1998).

    Article  PubMed  CAS  Google Scholar 

  2. Hance, K. W., Anderson, W. F., Devesa, S. S., Young, H. A. & Levine, P. H. Trends in inflammatory breast carcinoma incidence and survival: the Surveillance, Epidemiology, and End Results Program at the National Cancer Institute. J. Natl Cancer Inst. 97, 966–975 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Schlichting, J. A., Soliman, A. S., Schairer, C., Schottenfeld, D. & Merajver, S. D. Inflammatory and non-inflammatory breast cancer survival by socioeconomic position in the Surveillance, Epidemiology, and End Results database, 1990–2008. Breast Cancer Res. Treat. 134, 1257–1268 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fouad, T. M. et al. Inflammatory breast cancer: a proposed conceptual shift in the UICC-AJCC TNM staging system. Lancet Oncol. 18, e228–e232 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Anderson, W. F., Schairer, C., Chen, B. E., Hance, K. W. & Levine, P. H. Epidemiology of inflammatory breast cancer (IBC). Breast Dis. 22, 9–23 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Boussen, H. et al. Inflammatory breast cancer in Tunisia: epidemiological and clinical trends. Cancer 116, 2730–2735 (2010).

    Article  PubMed  Google Scholar 

  7. Bonnier, P. et al. Inflammatory carcinomas of the breast: a clinical, pathological, or a clinical and pathological definition? Int. J. Cancer 62, 382–385 (1995).

    Article  PubMed  CAS  Google Scholar 

  8. Manfrin, E. et al. Comparison between invasive breast cancer with extensive peritumoral vascular invasion and inflammatory breast carcinoma: a clinicopathologic study of 161 cases. Am. J. Pathol. 142, 299–306 (2014).

    Google Scholar 

  9. Charpin, C. et al. Inflammatory breast carcinoma: an immunohistochemical study using monoclonal anti-pHER-2/neu, pS2, cathepsin, ER and PR. Anticancer Res. 12, 591–597 (1992).

    PubMed  CAS  Google Scholar 

  10. Lehman, H. L. et al. Modeling and characterization of inflammatory breast cancer emboli grown in vitro. Int. J. Cancer 132, 2283–2294 (2013).

    Article  PubMed  CAS  Google Scholar 

  11. Xiao, Y. et al. The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction. Oncogene 30, 287–300 (2011).

    Article  PubMed  CAS  Google Scholar 

  12. Ye, Y. et al. Early to intermediate steps of tumor embolic formation involve specific proteolytic processing of E-cadherin regulated by Rab7. Mol. Cancer Res. 10, 713–726 (2012).

    Article  PubMed  CAS  Google Scholar 

  13. Charafe-Jauffret, E. et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin. Cancer Res. 16, 45–55 (2010). This study reports the expression of stem cell markers in IBC and their association with clinical outcome.

    Article  PubMed  CAS  Google Scholar 

  14. Li, J. et al. Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer. Oncologist 16, 1675–1683 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Masuda, H. et al. Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes. Ann. Oncol. 25, 384–391 (2014). This is the largest data set to show that the unique aggressive nature of IBC influences overall survival regardless of molecular subtype.

    Article  PubMed  CAS  Google Scholar 

  16. Kertmen, N. et al. Molecular subtypes in patients with inflammatory breast cancer; a single center experience. J. BUON 20, 35–39 (2015).

    PubMed  Google Scholar 

  17. Parton, M. et al. High incidence of HER-2 positivity in inflammatory breast cancer. Breast 13, 97–103 (2004).

    Article  PubMed  CAS  Google Scholar 

  18. Van der Auwera, I. et al. Integrated miRNA and mRNA expression profiling of the inflammatory breast cancer subtype. Br. J. Cancer 103, 532–541 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Lehman, H. L. et al. Regulation of inflammatory breast cancer cell invasion through Akt1/PKBalpha phosphorylation of RhoC GTPase. Mol. Cancer Res. 10, 1306–1318 (2012).

    Article  PubMed  CAS  Google Scholar 

  20. Masuda, H. et al. Comparison of molecular subtype distribution in triple-negative inflammatory and non-inflammatory breast cancers. Breast Cancer Res. 15, R112 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Dawood, S. et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann. Oncol. 22, 515–523 (2011).

    Article  PubMed  CAS  Google Scholar 

  22. Rosso, K. J. et al. Improved locoregional control in a contemporary cohort of nonmetastatic inflammatory breast cancer patients undergoing surgery. Ann. Surg. Oncol. 24, 2981–2988 (2017).

    Article  PubMed  Google Scholar 

  23. Ross, J. S. et al. Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations. Breast Cancer Res. Treat. 154, 152–162 (2015).

    Article  CAS  Google Scholar 

  24. Morrow, R. J., Etemadi, N., Yeo, B. & Ernst, M. Challenging a misnomer? The role of inflammatory pathways in inflammatory breast cancer. Mediators Inflamm. 2017, 4754827 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Arora, J. et al. Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies. Oncotarget 8, 25848–25863 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  26. S. M., R. et al. Immune and molecular determinants of response to neoadjuvant chemotherapy in inflammatory breast cancer. J. Clin. Oncol. 35, 11501 (2017).

    Article  Google Scholar 

  27. Iwamoto, T. et al. Different gene expressions are associated with the different molecular subtypes of inflammatory breast cancer. Breast Cancer Res. Treat. 125, 785–795 (2011).

    Article  PubMed  CAS  Google Scholar 

  28. Van Laere, S. et al. Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis. Br. J. Cancer 97, 1165–1174 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Van Laere, S. J. et al. Uncovering the molecular secrets of inflammatory breast cancer biology: an integrated analysis of three distinct Affymetrix gene expression datasets. Clin. Cancer Res. 19, 4685–4696 (2013). This study performs a comprehensive, systems biological analysis of IBC consortium genomic data in an attempt to uncover the genomic secrets of IBC.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Woodward, W. A. et al. Genomic and expression analysis of microdissected inflammatory breast cancer. Breast Cancer Res. Treat. 138, 761–772 (2013). This paper describes the microdissection of IBC in an attempt to eliminate the stromal effect on the genomics of IBC.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Bertucci, F. et al. Gene expression profiles of inflammatory breast cancer: correlation with response to neoadjuvant chemotherapy and metastasis-free survival. Ann. Oncol. 25, 358–365 (2014). This study reports a comprehensive analysis of IBC consortium genomic data, evaluating the difference in response to chemotherapy — a new approach to unravel the distinct genomics of IBC.

    Article  PubMed  CAS  Google Scholar 

  32. Lehmann, B. D. et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750–2767 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Manai, M. et al. MARCKS protein overexpression in inflammatory breast cancer. Oncotarget 8, 6246–6257 (2017).

    Article  PubMed  Google Scholar 

  34. Boersma, B. J. et al. A stromal gene signature associated with inflammatory breast cancer. Int. J. Cancer 122, 1324–1332 (2008).

    Article  PubMed  CAS  Google Scholar 

  35. Matsuda, N. et al. Identification of frequent somatic mutations in inflammatory breast cancer. Breast Cancer Res. Treat. 163, 263–272 (2017).

    Article  PubMed  CAS  Google Scholar 

  36. Debeb, B. G. et al. EZH2 expression correlates with locoregional recurrence after radiation in inflammatory breast cancer. J. Exp. Clin. Cancer Res. 33, 58 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Putcha, P. et al. HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers. Breast Cancer Res. 17, 149 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Lee, J. et al. A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression. Breast Cancer Res. Treat. 146, 259–272 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lim, B. et al. Open-label phase 1b study of entinostat, and lapatinib alone, and in combination with trastuzumab in patients with HER2+ metastatic breast cancer after progression on trastuzumab [abstract]. J. Clin. Oncol. 34 (Suppl.), 609 (2016).

    Article  Google Scholar 

  40. Debeb, B. G. et al. Histone deacetylase inhibitor-induced cancer stem cells exhibit high pentose phosphate pathway metabolism. Oncotarget 7, 28329–28339 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Maltseva, D. V. et al. miRNome of inflammatory breast cancer. BMC Res. 7, 871 (2014).

    Article  CAS  Google Scholar 

  42. Huo, L. et al. MicroRNA expression profiling identifies decreased expression of miR-205 in inflammatory breast cancer. Mod. Path. 29, 330–346 (2016).

    Article  CAS  Google Scholar 

  43. Anfossi, S. et al. High serum miR-19a levels are associated with inflammatory breast cancer and are predictive of favorable clinical outcome in patients with metastatic HER2+ inflammatory breast cancer. PLoS ONE 9, e83113 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Mesci, A. et al. Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis. Br. J. Cancer 116, 1350–1357 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Rokavec, M., Li, H., Jiang, L. & Hermeking, H. The p53/miR-34 axis in development and disease. J. Mol. Cell. Biol. 6, 214–230 (2014).

    Article  PubMed  CAS  Google Scholar 

  46. Lerebours, F. et al. miRNA expression profiling of inflammatory breast cancer identifies a 5-miRNA signature predictive of breast tumor aggressiveness. Int. J. Cancer 133, 1614–1623 (2013).

    Article  PubMed  CAS  Google Scholar 

  47. Debeb, B. G. et al. miR-141-mediated regulation of brain metastasis from breast cancer. J. Natl. Cancer Inst. 108, djw026 (2016). This study shows that a specific miRNA mediates one of the most aggressive metastatic patterns in IBC.

    Article  PubMed Central  CAS  Google Scholar 

  48. Van Laere, S., Limame, R., Van Marck, E. A., Vermeulen, P. B. & Dirix, L. Y. Is there a role for mammary stem cells in inflammatory breast carcinoma?: a review of evidence from cell line, animal model, and human tissue sample experiments. Cancer 116, 2794–2805 (2010).

    Article  PubMed  CAS  Google Scholar 

  49. Gong, Y. et al. Aldehyde dehydrogenase 1 expression in inflammatory breast cancer as measured by immunohistochemical staining. Clin. Breast Cancer 14, e81–88 (2014).

    Article  PubMed  CAS  Google Scholar 

  50. Rosenthal, D. T. et al. RhoC impacts the metastatic potential and abundance of breast cancer stem cells. PLoS ONE 7, e40979 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. van Golen, K. L. et al. Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer. Clin. Exp. Metastasis 19, 301–311 (2002).

    Article  PubMed  Google Scholar 

  52. Wynn, M. L. et al. RhoC GTPase is a potent regulator of glutamine metabolism and N-acetylaspartate production in inflammatory breast cancer cells. J. Biol Chem. 291, 13715–13729 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. W. & Merajver, S. D. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 60, 5832–5838 (2000).

    PubMed  Google Scholar 

  54. Arias-Pulido, H. et al. SRC-1 expression is a prognostic factor of breast cancer-specific and disease-free survival in inflammatory breast cancer [abstract]. Cancer Res. 71 (Suppl.), P4-01-19 (2011).

  55. Herold, C. I. et al. Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing. Clin. Cancer Res. 17, 6061–6070 (2011).

    Article  PubMed  CAS  Google Scholar 

  56. Wolfe, A. R. et al. High-density and very-low-density lipoprotein have opposing roles in regulating tumor-initiating cells and sensitivity to radiation in inflammatory breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 91, 1072–1080 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Lacerda, L. et al. Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl Med. 3, 849–856 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Denoyelle, C. et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis 22, 1139–1148 (2001).

    Article  PubMed  CAS  Google Scholar 

  59. Park, Y. H., Jung, H. H., Ahn, J. S. & Im, Y. H. Statin induces inhibition of triple negative breast cancer (TNBC) cells via PI3K pathway. Biochem. Biophys. Res. Commun. 439, 275–279 (2013).

    Article  PubMed  CAS  Google Scholar 

  60. Wang, J. & Kitajima, I. Pitavastatin inactivates NF-kappaB and decreases IL-6 production through Rho kinase pathway in MCF-7 cells. Oncol. Rep. 17, 1149–1154 (2007).

    PubMed  CAS  Google Scholar 

  61. Klawitter, J., Shokati, T., Moll, V., Christians, U. & Klawitter, J. Effects of lovastatin on breast cancer cells: a proteo-metabonomic study. Breast Cancer Res. 12, R16 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Ghosh-Choudhury, N., Mandal, C. C., Ghosh-Choudhury, N. & Ghosh Choudhury, G. Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth. Cell. Signal. 22, 749–758 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Gopalan, A., Yu, W., Sanders, B. G. & Kline, K. Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway. Cancer Lett. 329, 9–16 (2013).

    Article  PubMed  CAS  Google Scholar 

  64. Campbell, M. J. et al. Breast cancer growth prevention by statins. Cancer Res. 66, 8707–8714 (2006).

    Article  PubMed  CAS  Google Scholar 

  65. Wolfe, A. R. et al. Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models. Oncotarget 7, 82482–82492 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lacerda, L. et al. Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model. Breast Cancer Res. 17, 42 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Wolfe, A. R. et al. Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res. Treat. 154, 495–508 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Nelson, E. R. et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342, 1094–1098 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Van den Eynden, G. G. et al. Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer. Breast Cancer Res. Treat. 95, 219–228 (2006).

    Article  PubMed  CAS  Google Scholar 

  70. Joglekar, M., Elbazanti, W. O., Weitzman, M. D., Lehman, H. L. & van Golen, K. L. Caveolin-1 mediates inflammatory breast cancer cell invasion via the Akt1 pathway and RhoC GTPase. J. Cell. Biochem. 116, 923–933 (2015).

    Article  PubMed  CAS  Google Scholar 

  71. Wang, X. et al. TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Res. 73, 6516–6525 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. Van der Auwera, I. et al. Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification. Clin. Cancer Res. 10, 7965–7971 (2004).

    Article  PubMed  Google Scholar 

  73. Van der Auwera, I. et al. Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin. Cancer Res. 11, 7637–7642 (2005).

    Article  PubMed  CAS  Google Scholar 

  74. Wedam, S. B. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769–777 (2006).

    Article  PubMed  CAS  Google Scholar 

  75. Bertucci, F. et al. Bevacizumab plus neoadjuvant chemotherapy in patients with HER2-negative inflammatory breast cancer (BEVERLY-1): a multicentre, single-arm, phase 2 study. Lancet Oncol. 17, 600–611 (2016).

    Article  PubMed  CAS  Google Scholar 

  76. Pierga, J. Y. et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Lancet Oncol. 13, 375–384 (2012).

    Article  PubMed  CAS  Google Scholar 

  77. Levine, P. H. et al. Evaluation of lymphangiogenic factors, vascular endothelial growth factor D and E-cadherin in distinguishing inflammatory from locally advanced breast cancer. Clin. Breast Cancer 12, 232–239 (2012).

    Article  PubMed  CAS  Google Scholar 

  78. Raposo, T. P., Pires, I., Prada, J., Queiroga, F. L. & Argyle, D. J. Exploring new biomarkers in the tumour microenvironment of canine inflammatory mammary tumours. Vet. Comp. Oncol. 15, 655–666 (2016).

    Article  PubMed  CAS  Google Scholar 

  79. Oladapo, H. O. et al. Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells. Cancer Lett. 411, 136–149 (2017).

    Article  PubMed  CAS  Google Scholar 

  80. Kenny, P. A. et al. The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol. Oncol. 1, 84–96 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Cabioglu, N. et al. Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann. Oncol. 18, 1021–1029 (2007).

    Article  PubMed  CAS  Google Scholar 

  82. Zhang, D. et al. Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Clin. Cancer Res. 15, 6639–6664 (2009). This manuscript reports that EGFR signalling is active in IBC and is the basis of an ongoing randomized phase II study evaluating panitumumab.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sauer, S. J. et al. Bisphenol A activates EGFR and ERK promoting proliferation, tumor spheroid formation and resistance to EGFR pathway inhibition in estrogen receptor-negative inflammatory breast cancer cells. Carcinogenesis 38, 252–260 (2017).

    Article  PubMed  CAS  Google Scholar 

  84. Silvera, D. & Schneider, R. J. Inflammatory breast cancer cells are constitutively adapted to hypoxia. Cell Cycle 8, 3091–3096 (2009).

    Article  PubMed  CAS  Google Scholar 

  85. Vermeulen, P. B., Van Laere, S. J. & Dirix, L. Y. Inflammatory breast carcinoma as a model of accelerated self-metastatic expansion by intravascular growth. Br. J. Cancer 101, 1028–1029 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Jolly, M. K. et al. Inflammatory breast cancer: a model for investigating cluster-based dissemination. npj Breast Cancer 3, 21 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Topalian, S. L., Weiner, G. J. & Pardoll, D. M. Cancer immunotherapy comes of age. J. Clin. Oncol. 29, 4828–4836 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Cimino-Mathews, A. et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum. Pathol. 47, 52–63 (2016).

    Article  PubMed  CAS  Google Scholar 

  89. Hamm, C. A. et al. Genomic and immunological tumor profiling identifies targetable pathways and extensive CD8+ /PDL1+ immune infiltration in inflammatory breast cancer tumors. Mol. Cancer Ther. 15, 1746–1756 (2016).

    Article  PubMed  CAS  Google Scholar 

  90. Jhaveri, K. et al. Hyperactivated mTOR and JAK2/STAT3 pathways: molecular drivers and potential therapeutic targets of inflammatory and invasive ductal breast cancers after neoadjuvant chemotherapy. Clin. Breast Cancer 16, 113–122.e1 (2016).

    Article  PubMed  CAS  Google Scholar 

  91. Su, S. et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25, 605–620 (2014).

    Article  PubMed  CAS  Google Scholar 

  92. Bochet, L. et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 73, 5657–5668 (2013).

    Article  PubMed  CAS  Google Scholar 

  93. Oleinika, K., Nibbs, R. J., Graham, G. J. & Fraser, A. R. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin. Exp. Immun. 171, 36–45 (2013).

    Article  PubMed  CAS  Google Scholar 

  94. Schmidt, T., Ben-Batalla, I., Schultze, A. & Loges, S. Macrophage-tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands. Cell. Mol. Life Sci. 69, 1391–1414 (2012).

    Article  PubMed  CAS  Google Scholar 

  95. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Sica, A. Macrophages give Gas(6) to cancer. Blood 115, 2122–2123 (2010).

    Article  PubMed  CAS  Google Scholar 

  97. Mego, M. et al. Circulating tumor cells (CTCs) are associated with abnormalities in peripheral blood dendritic cells in patients with inflammatory breast cancer. Oncotarget 8, 35656–35658 (2016).

    PubMed Central  Google Scholar 

  98. Bertucci, F. et al. PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget 6, 13506–13519 (2015). This study is the first analysis of residual IBC after neoadjuvant chemotherapy and searches for relevant biomarkers, including those related to the microenvironment.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Datta, J. et al. Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer. Breast Cancer Res. 17, 71 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Cohen, N. et al. Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1. Oncogene 36, 4457–4468 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Baroni, S. et al. Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts. Cell Death Dis. 7, e2312 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Zhang, Z. et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett. 397, 33–42 (2017).

    Article  PubMed  CAS  Google Scholar 

  103. Colpaert, C. G. et al. Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression. Br. J. Cancer 88, 718–725 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Goswami, S. & Sharma-Walia, N. Osteoprotegerin secreted by inflammatory and invasive breast cancer cells induces aneuploidy, cell proliferation and angiogenesis. BMC Cancer 15, 935 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Aaronson, D. S. & Horvath, C. M. A road map for those who don’t know JAK-STAT. Science 296, 1653–1655 (2002).

    Article  PubMed  CAS  Google Scholar 

  106. Ogony, J., Choi, H. J., Lui, A., Cristofanilli, M. & Lewis-Wambi, J. Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res. 18, 25 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02041429 (2017).

  108. Bieche, I. et al. Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature. Clin. Cancer Res. 10, 6789–6795 (2004).

    Article  PubMed  CAS  Google Scholar 

  109. Marotta, L. L. et al. The JAK2/STAT3 signaling pathway is required for growth of CD44( + )CD24(-) stem cell-like breast cancer cells in human tumors. J. Clin. Invest. 121, 2723–2735 (2011). This manuscript reports a connection between stem cell markers and hyperactivated JAK–STAT signalling, which could lead to translational drug development. Currently, a clinical trial is ongoing to study the clinical efficacy of a JAK inhibitor on the basis of this study.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Kim, H. S. et al. COX2 overexpression is a prognostic marker for Stage III breast cancer. Breast Cancer Res. Treat. 132, 51–59 (2012).

    Article  PubMed  CAS  Google Scholar 

  111. Ristimaki, A. et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 62, 632–635 (2002).

    PubMed  CAS  Google Scholar 

  112. Wang, X. et al. EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer. Oncotarget 8, 67904–67917 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Subbaramaiah, K. et al. Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov. 2, 356–365 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Lee, J., Banu, S. K., Burghardt, R. C., Starzinski-Powitz, A. & Arosh, J. A. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits adhesion of human endometriotic epithelial and stromal cells through suppression of integrin-mediated mechanisms. Biol. Reprod. 88, 77 (2013).

    PubMed  Google Scholar 

  116. Robertson, F. M. et al. Differential regulation of the aggressive phenotype of inflammatory breast cancer cells by prostanoid receptors EP3 and EP4. Cancer 116, 2806–2814 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Zheng, Z. et al. Correlation between epidermal growth factor receptor and tumor stem cell markers CD44/CD24 and their relationship with prognosis in breast invasive ductal carcinoma. Med. Oncol. 32, 275 (2015).

    Article  PubMed  CAS  Google Scholar 

  118. Mu, Z. et al. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models. J. Exp. Clin. Cancer Res. 33, 47 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Matsuda, N. et al. Phase II study of panitumumab, nab-paclitaxel, and carboplatin followed by FEC neoadjuvant chemotherapy for patients with primary HER-2 negative inflammatory breast cancer [abstract]. J. Clin. Oncol. 33 (Suppl.), 1087 (2015).

    Google Scholar 

  120. Joglekar-Javadekar, M. et al. Characterization and targeting of platelet-derived growth factor receptor alpha (PDGFRA) in inflammatory breast cancer (IBC). Neoplasia 19, 564–573 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Dong, J. et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. J. EMBO 23, 2800–2810 (2004).

    Article  CAS  Google Scholar 

  122. Jechlinger, M. et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Invest. 116, 1561–1570 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Seymour, L. & Bezwoda, W. R. Positive immunostaining for platelet derived growth factor (PDGF) is an adverse prognostic factor in patients with advanced breast cancer. Breast Cancer Res. Treat. 32, 229–233 (1994).

    Article  PubMed  CAS  Google Scholar 

  124. Carvalho, I., Milanezi, F., Martins, A., Reis, R. M. & Schmitt, F. Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res. 7, R788–795 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Drygin, D. et al. Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer. Biochem. Biophys. Res. Commun. 415, 163–167 (2011).

    Article  PubMed  CAS  Google Scholar 

  126. Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Mahooti, S. et al. Breast carcinomatous tumoral emboli can result from encircling lymphovasculogenesis rather than lymphovascular invasion. Oncotarget 1, 131–147 (2010).

    PubMed  PubMed Central  Google Scholar 

  128. Babaei, Z. et al. Relationship of obesity with serum concentrations of leptin, CRP and IL-6 in breast cancer survivors. J. Egypt. Natl Canc. Inst. 27, 223–229 (2015).

    Article  PubMed  Google Scholar 

  129. Markkula, A., Simonsson, M., Ingvar, C., Rose, C. & Jernstrom, H. IL6 genotype, tumour ER-status, and treatment predicted disease-free survival in a prospective breast cancer cohort. BMC Cancer 14, 759 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Ammanamanchi, S., Kim, S. J., Sun, L. Z. & Brattain, M. G. Induction of transforming growth factor-beta receptor type II expression in estrogen receptor-positive breast cancer cells through SP1 activation by 5-aza-2′-deoxycytidine. J. Biol. Chem. 273, 16527–16534 (1998).

    Article  PubMed  CAS  Google Scholar 

  131. Ellis, D. L. & Teitelbaum, S. L. Inflammatory carcinoma of the breast. A pathologic definition. Cancer 33, 1045–1047 (1974).

    Article  PubMed  CAS  Google Scholar 

  132. Ohshiro, K., Schwartz, A. M., Levine, P. H. & Kumar, R. Alternate estrogen receptors promote invasion of inflammatory breast cancer cells via non-genomic signaling. PLoS ONE 7, e30725 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Anderson, W. F., Chu, K. C. & Chang, S. Inflammatory breast carcinoma and noninflammatory locally advanced breast carcinoma: distinct clinicopathologic entities? J. Clin. Oncol. 21, 2254–2259 (2003).

    Article  PubMed  Google Scholar 

  134. Fernandez, S. V. et al. Inflammatory breast cancer (IBC): clues for targeted therapies. Breast Cancer Res. Treat. 140, 23–33 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Wang, L., Zuo, X., Xie, K. & Wei, D. The role of CD44 and cancer stem cells. Methods Mol. Biol. 1692, 31–42 (2018).

    Article  PubMed  CAS  Google Scholar 

  136. Fei, M. et al. TNF-alpha from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection. Proc. Natl Acad. Sci. USA 108, 5360–5365 (2011).

    Article  PubMed  Google Scholar 

  137. Hilkens, C. M., Kalinski, P., de Boer, M. & Kapsenberg, M. L. Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. Blood 90, 1920–1926 (1997).

    PubMed  CAS  Google Scholar 

  138. Hallahan, D. E., Spriggs, D. R., Beckett, M. A., Kufe, D. W. & Weichselbaum, R. R. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc. Natl Acad. Sci. USA 86, 10104–10107 (1989).

    Article  PubMed  CAS  Google Scholar 

  139. Curran, E. et al. STING pathway activation stimulates potent immunity against acute myeloid leukemia. Cell Rep. 15, 2357–2366 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Alpaugh, M. L., Tomlinson, J. S., Shao, Z. M. & Barsky, S. H. A novel human xenograft model of inflammatory breast cancer. Cancer Res. 59, 5079–5084 (1999).

    PubMed  CAS  Google Scholar 

  141. Kurebayashi, J. et al. Isolation and characterization of a new human breast cancer cell line, KPL-4, expressing the Erb B family receptors and interleukin-6. Br. J. Cancer 79, 707–717 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Hall, C. S. et al. Novel inflammatory breast cancer cell line, MDA-IBC-1 expresses and secretes WISP3, a putative tumor suppressor in inflammatory breast cancer [abstract]. Cancer Res. 69 (Suppl.), 1051 (2009).

    Article  Google Scholar 

  143. Klopp, A. H. et al. Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells. PLoS ONE 5, e12180 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Nokes, B. T. et al. In vitro assessment of the inflammatory breast cancer cell line SUM 149: discovery of 2 single nucleotide polymorphisms in the RNase L gene. J. Cancer 4, 104–116 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Holliday, D. L. & Speirs, V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 13, 215 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Shirakawa, K. et al. Inflammatory breast cancer: vasculogenic mimicry and its hemodynamics of an inflammatory breast cancer xenograft model. Breast Cancer Res. 5, 136–139 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health (NIH) grant 1R01CA205043-01A1 (N.T.U.), the Morgan Welch Inflammatory Breast Cancer Research Program, the Breast Cancer Research Foundation (N.T.U.), the State of Texas Rare and Aggressive Breast Cancer Research Program (N.T.U.), the MD Anderson Cancer Center Support Grant from the US National Cancer Institute (CA016672), which supports the Biostatistics Shared Resource, and the US National Cancer Institute grant CA079466. D. Chalaire of the Department of Scientific Publications at MD Anderson Cancer Center provided scientific editing services.

Author information

Authors and Affiliations

  1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bora Lim, Xiaoping Wang & Naoto T. Ueno

  2. Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bora Lim, Wendy A. Woodward, Xiaoping Wang, James M. Reuben & Naoto T. Ueno

  3. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Wendy A. Woodward

  4. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    James M. Reuben

Authors
  1. Bora Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wendy A. Woodward
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James M. Reuben
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoto T. Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.L. researched data for the article. N.T.U., B.L. and W.A.W. made a substantial contribution to the discussion of content. B.L., W.A.W., X.W. and J.M.R. wrote the article. All authors reviewed and/or edited the article before submission. The order of authorship is B.L., W.A.W., X.W., J.M.R. and N.T.U.

Corresponding authors

Correspondence to Bora Lim or Naoto T. Ueno.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Glossary

Tumour emboli

Clusters of cancer cells that directly invade dermal–lymphatic vessels or other lymphatic vessels, causing inflammation, breast oedema and lymph node metastasis.

Chemotherapy-resistant dormant units

Units of cells with a 3D composition that mimics the normal gland structure within breast tissue. Formation of an acinar structure in cancer cells has been associated with chemotherapy resistance.

Tumour microenvironment

(TME). The cellular environment in which cancer cells exist, which includes other cell types and components, such as blood vessels, immune cells, fibroblasts, bone marrow-derived stromal cells, signalling molecules and extracellular matrix.

Pathological complete response

(pCR). A category of histopathological post-neoadjuvant therapy response assessment that is often defined as the absence of invasive and/or in situ residual tumours within breast tissue and lymph nodes. Achieving pCR can predict favourable long-term clinical outcomes.

Vascular patency

The degree to which blood vessels are not blocked or obstructed.

Endocrine therapy

Treatment that adds, blocks or removes hormones. Endocrine therapy can be used as single or combination therapy for hormone receptor (HR)-positive breast cancer but has limited activity against HR-positive inflammatory breast cancer.

Synoikis

The activation of survival signals through junctional adhesions between neighbouring cells.

Anoikis

The induction of apoptosis owing to detachment from the extracellular matrix.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lim, B., Woodward, W.A., Wang, X. et al. Inflammatory breast cancer biology: the tumour microenvironment is key. Nat Rev Cancer 18, 485–499 (2018). https://doi.org/10.1038/s41568-018-0010-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-018-0010-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer