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:

Molecular targets for treatment of inflammatory breast cancer

Nature Reviews Clinical Oncology volume 6, pages 387–394 (2009)Cite this article

Abstract

Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with inflammatory breast cancer (IBC) remains poor. Therapies that target vasculolymphatic processes—angiogenesis, lymphangiogenesis, and vasculogenesis—have shown potential in the treatment for IBC, as represented by bevacizumab. Although the therapeutic effect of targeting lymphangiogenesis and vasculogenesis requires further investigation, targeting of angiogenesis has potential, not only through true antiangiogenic effects, but also through antitumor effects in concert with other pathways. Therapies that target cell proliferation pathways are the most promising targeted therapies for IBC. In particular, therapies that target human epidermal growth factor receptor 2 (for example, trastuzumab and lapatinib) have performed well in the clinical setting, leading to improved outcomes for patients with IBC. Metastatic pathways could have a unique, key role in the aggressiveness of the IBC phenotype. Further extensive work on the unique molecular characteristics of IBC is essential to ensure improved outcomes for patients with this disease. In this Review we discuss three pathways—vasculolymphatic, cell proliferation and metastatic—that could represent important targets in the treatment of IBC.

Key Points

  • Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with inflammatory breast cancer (IBC) remains poor

  • Targeted therapies directed against molecular targets in vasculolymphatic pathways—those involved in angiogenesis, lymphangiogenesis, and vasculogenesis—have yielded promising results in IBC in preclinical studies

  • Drugs that target human epidermal growth factor receptor 2 (such as trastuzumab and lapatinib) have shown favorable results, leading to improved outcomes for patients with IBC

  • Identification of molecular findings unique to IBC need to be discovered

  • Further extensive preclinical and clinical work based on molecular findings is needed to improve outcomes in patients with IBC

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

Figure 1: Endothelial cell pathways.
Figure 2: Cancer cell pathways.

Similar content being viewed by others

References

  1. Gonzalez-Angulo, A. M. et al. Trends for inflammatory breast cancer: is survival improving? Oncologist 12, 904–912 (2007).

    Article  PubMed  Google Scholar 

  2. Hance, K. W. et al. 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  Google Scholar 

  3. Yang, C. H. & Cristofanilli, M. The role of p53 mutations as a prognostic factor and therapeutic target in inflammatory breast cancer. Future Oncol. 2, 247–255 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. 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  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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  CAS  PubMed  Google Scholar 

  6. Shirakawa, K. et al. Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer. Int. J. Cancer 99, 344–351 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. 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  CAS  PubMed  Google Scholar 

  8. McCarthy, N. J. et al. Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer. Clin. Cancer Res. 8, 3857–3862 (2002).

    CAS  PubMed  Google Scholar 

  9. 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  CAS  PubMed  Google Scholar 

  10. Yang, C. H. & Cristofanilli, M. Systemic treatments for inflammatory breast cancer. Breast Dis. 22, 55–65 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Weigand, M. et al. Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis 8, 197–204 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Bernstein, J. A. & Mehta, R. In vivo response-adapted dose-dense (dd) doxorubicin and cyclophosphamide (AC) -> weekly carboplatin and albumin-bound paclitaxel (nab-TC)/trastuzumab (H)/bevacizumab (B) in large and inflammatory breast cancer (BC): a phase II study [abstract]. J. Clin. Oncol. 25, 11078 (2007).

    Google Scholar 

  13. Overmoyer, B. et al. Inflammatory breast cancer as a model disease to study tumor angiogenesis: results of a phase IB trial of combination SU5416 and doxorubicin. Clin. Cancer Res. 13, 5862–5868 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Achen, M. G. et al. Targeting lymphangiogenesis to prevent tumour metastasis. Br. J. Cancer 94, 1355–1360 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Roberts, N. et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 66, 2650–2657 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Shirakawa, K. et al. Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res. 61, 445–451 (2001).

    CAS  PubMed  Google Scholar 

  19. Shirakawa, K. et al. Vasculogenic mimicry and pseudo-comedo formation in breast cancer. Int. J. Cancer 99, 821–828 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Dawood, S. et al. Prognostic significance of HER-2 status in women with inflammatory breast cancer. Cancer 112, 1905–1911 (2008).

    Article  PubMed  Google Scholar 

  22. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Dawood, S. et al. Efficacy and safety of neoadjuvant trastuzumab combined with paclitaxel and epirubicin: a retrospective review of the M. D. Anderson experience. Cancer 110, 1195–1200 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Limentani, S. A. et al. Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer. J. Clin. Oncol. 25, 1232–1238 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Hurley, J. et al. Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J. Clin. Oncol. 24, 1831–1838 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Van Pelt, A. E. et al. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin. Breast Cancer 4, 348–353 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Dawood, S. et al. HER-2 positive inflammatory breast cancer (IBC): high pathological response rate with trastuzumab-based neoadjuvant chemotherapy. Presented at the San Antonio Breast Cancer Symposium 2007, December 13–16, San Antonio, TX (2007).

  29. Baselga, J. et al. Efficacy of neoadjuvant trastuzumab in patients with inflammatory breast cancer (IBC): data from the NOAH (Neoadjuvant Herceptin) phase III trial [abstract]. Proc. ECCO 2007.

  30. Cristofanilli, M. et al. A phase II combination study of lapatinib and paclitaxel as a neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer [abstract]. Breast Cancer Res. 100, a1 (2006).

    Google Scholar 

  31. Johnston, S. et al. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J. Clin. Oncol. 26, 1066–1072 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Guerin, M. et al. Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance. Int. J. Cancer 43, 201–208 (1989).

    Article  CAS  PubMed  Google Scholar 

  33. Kleer, C. G. et al. WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer. Breast Cancer Res. 6, R110–R115 (2004).

    Article  PubMed  Google Scholar 

  34. Stratford, A. L. et al. Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy. Breast Cancer Res. 9, R61 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Willmarth, N. E. & Ethier, S. P. Autocrine and juxtacrine effects of amphiregulin on the proliferative, invasive, and migratory properties of normal and neoplastic human mammary epithelial cells. J. Biol. Chem. 281, 37728–37737 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Lev, D. C. et al. Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells. Br. J. Cancer 91, 795–802 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Spector, N. et al. HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors. Breast Cancer Res. 9, 205 (2007).

    Article  PubMed Central  Google Scholar 

  38. van Golen, K. L. et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin. Cancer Res. 5, 2511–2519 (1999).

    CAS  PubMed  Google Scholar 

  39. Davies, S. R. et al. Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer. Ann. Surg. Oncol. 14, 1909–1918 (2007).

    Article  PubMed  Google Scholar 

  40. Hwa, V. et al. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr. Rev. 20, 761–787 (1999).

    CAS  PubMed  Google Scholar 

  41. Kleer, C. G. et al. WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene 21, 3172–3180 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Ridley, A. J. The GTP-binding protein Rho. Int. J. Biochem. Cell Biol. 29, 1225–1229 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. van Golen, K. L. et al. 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).

    CAS  PubMed  Google Scholar 

  45. van Golen, K. L. et al. Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor. Mol. Cancer Ther. 1, 575–583 (2002).

    CAS  PubMed  Google Scholar 

  46. Suwa, H. et al. Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br. J. Cancer 77, 147–152 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kleer, C. G. et al. RhoC-GTPase is a novel tissue biomarker associated with biologically aggressive carcinomas of the breast. Breast Cancer Res. Treat. 93, 101–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Rowinsky, E. K. et al. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J. Clin. Oncol. 17, 3631–3652 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Cohen, L. H. et al. Inhibitors of prenylation of Ras and other G-proteins and their application as therapeutics. Biochem. Pharmacol. 60, 1061–1068 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Gonzalez-Angulo, A. M. et al. Downregulation of the cyclin-dependent kinase inhibitor p27kip1 might correlate with poor disease-free and overall survival in inflammatory breast cancer. Clin. Breast Cancer 7, 326–330 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. 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  CAS  PubMed  Google Scholar 

  53. Huang, H. et al. Inhibition of primary tumor growth and distant metastasis with a CXCR4 antagonist in a mouse model of breast cancer. [abstract 5743]. AACR Meeting Abstracts 2007.

    Google Scholar 

  54. Sarrio, D. et al. Epithelial–mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989–997 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Thiery, J. P. & Morgan, M. Breast cancer progression with a Twist. Nat. Med. 10, 777–778 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Tomlinson, J. S. et al. An intact overexpressed E-cadherin/alpha, beta-catenin axis characterizes the lymphovascular emboli of inflammatory breast carcinoma. Cancer Res. 61, 5231–5241 (2001).

    CAS  PubMed  Google Scholar 

  57. Kleer, C. G. et al. Persistent E-cadherin expression in inflammatory breast cancer. Mod. Pathol. 14, 458–464 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Nguyen, D. M. et al. Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype. Clin. Cancer Res. 12, 5047–5054 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Charafe-Jauffret, E. et al. Immunophenotypic analysis of inflammatory breast cancers: identification of an 'inflammatory signature'. J. Pathol. 202, 265–273 (2004).

    Article  PubMed  Google Scholar 

  60. Garcia, S. et al. c-Met overexpression in inflammatory breast carcinomas: automated quantification on tissue microarrays. Br. J. Cancer 96, 329–335 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dong, H. M. et al. Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro. J. Cancer Res. Clin. Oncol. 133, 83–92 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Aggarwal, B. B. Nuclear factor-kappaB: the enemy within. Cancer Cell 6, 203–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Karin, M. et al. NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2, 301–310 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Van Laere, S. J. et al. Nuclear factor-kappaB signature of inflammatory breast cancer by cDNA microarray validated by quantitative real-time reverse transcription-PCR, immunohistochemistry, and nuclear factor-kappaB DNA-binding. Clin. Cancer Res. 12, 3249–3256 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Van Laere, S. et al. Distinct molecular signature of inflammatory breast cancer by cDNA microarray analysis. Breast Cancer Res. Treat. 93, 237–246 (2005).

    Article  PubMed  Google Scholar 

  66. Lee, C. H. et al. NF-kappaB as a potential molecular target for cancer therapy. Biofactors 29, 19–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Schmid, P. et al. A phase I/II study of bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines. Ann. Oncol. 19, 871–876 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Zhou, Y. et al. The NFkappaB pathway and endocrine-resistant breast cancer. Endocr. Relat. Cancer 12 (Suppl. 1), S37–S46 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Gonzalez-Angulo, A. M. et al. p53 expression as a prognostic marker in inflammatory breast cancer. Clin. Cancer Res. 10, 6215–6221 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Faille, A. et al. p53 mutations and overexpression in locally advanced breast cancers. Br. J. Cancer 69, 1145–1150 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Turpin, E. et al. Increased incidence of ERBB2 overexpression and TP53 mutation in inflammatory breast cancer. Oncogene 21, 7593–7597 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Sawaki, M. et al. High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer. Breast Cancer 13, 172–178 (2006).

    Article  PubMed  Google Scholar 

  73. Kandioler-Eckersberger, D. et al. TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin. Cancer Res. 6, 50–56 (2000).

    CAS  PubMed  Google Scholar 

  74. Miller, L. D. et al. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc. Natl Acad. Sci. USA 102, 13550–13555 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Stephanie Deming of the Department of Scientific Publications at M. D. Anderson Cancer Center Houston, TX, for her expert editorial assistance. This work was supported in part by a Morgan Welch Inflammatory Breast Cancer Grant (M.C., N.T.U.).

Author information

Authors and Affiliations

  1. St Luke's International Hospital, Tokyo, Japan

    Hideko Yamauchi & Seigo Nakamura

  2. Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Massimo Cristofanilli, Gabriel N. Hortobagyi & Naoto T. Ueno

Authors
  1. Hideko Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massimo Cristofanilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seigo Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriel N. Hortobagyi
    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

Corresponding author

Correspondence to Naoto T. Ueno.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamauchi, H., Cristofanilli, M., Nakamura, S. et al. Molecular targets for treatment of inflammatory breast cancer. Nat Rev Clin Oncol 6, 387–394 (2009). https://doi.org/10.1038/nrclinonc.2009.73

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2009.73

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing