Tumor Biology

, Volume 32, Issue 4, pp 787–799 | Cite as

The impact of caveolin protein expression in tumor stroma on prognosis of breast cancer

  • Ja Seung Koo
  • Seho Park
  • Seung Il Kim
  • Sarah Lee
  • Byeong-Woo Park
Research Article


We aimed to investigate the expression of caveolin-1, -2, -3, and platelet-derived growth factor (PDGF) β receptor in breast cancer cells and stroma by immunohistochemistry and to analyze their implications. The expression rates of stromal caveolin-2 and PDGF β receptor increased as the tumor progressed from ductal carcinoma in situ to microinvasive ductal carcinoma, intraductal component of invasive ductal carcinoma (IDC), and IDC (p < 0.001). The expression loss of caveolin-1 in tumor stroma of IDC correlated with high tumor stage (p < 0.001), high nodal stage (p = 0.011), high cancer stage (p = 0.005), estrogen receptor negativity (p = 0.003), and tumor recurrence (p = 0.003). In addition, the expression loss of caveolin-1 in tumor stroma was correlated with a shorter disease-free survival and an overall survival (p < 0.001). In conclusion, the loss of stromal caveolin-1 is related to poor prognosis in IDC.


Breast cancer Caveolin Immunohistochemistry Stroma 


Conflicts of interest



  1. 1.
    Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46–54. doi: 10.1038/35094059.PubMedCrossRefGoogle Scholar
  2. 2.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401. doi: 10.1038/nrc1877.PubMedCrossRefGoogle Scholar
  3. 3.
    Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332–7. doi: 10.1038/nature03096.PubMedCrossRefGoogle Scholar
  4. 4.
    Mueller MM, Fusenig NE. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4(11):839–49. doi: 10.1038/nrc1477.PubMedCrossRefGoogle Scholar
  5. 5.
    Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. 2006;5(15):1597–601.PubMedCrossRefGoogle Scholar
  6. 6.
    Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet. 2009;25(1):30–8. doi: 10.1016/j.tig.2008.10.012.PubMedCrossRefGoogle Scholar
  7. 7.
    Ma XJ, Dahiya S, Richardson E, Erlander M, Sgroi DC. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res. 2009;11(1):R7. doi: 10.1186/bcr2222.PubMedCrossRefGoogle Scholar
  8. 8.
    Mercier I, Casimiro MC, Wang C, Rosenberg AL, Quong J, Minkeu A, et al. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: implications for the response to hormonal therapy. Cancer Biol Ther. 2008;7(8):1212–25.PubMedCrossRefGoogle Scholar
  9. 9.
    Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res. 1999;250(2):273–83. doi: 10.1006/excr.1999.4543.PubMedCrossRefGoogle Scholar
  10. 10.
    Casey T, Bond J, Tighe S, Hunter T, Lintault L, Patel O, et al. Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Res Treat. 2009;114(1):47–62. doi: 10.1007/s10549-008-9982-8.PubMedCrossRefGoogle Scholar
  11. 11.
    Lisanti MP, Scherer PE, Tang Z, Sargiacomo M. Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol. 1994;4(7):231–5. doi: 10.1016/0962-8924(94)90114-7.PubMedCrossRefGoogle Scholar
  12. 12.
    Lisanti MP, Tang Z, Scherer PE, Kubler E, Koleske AJ, Sargiacomo M. Caveolae, transmembrane signalling and cellular transformation. Mol Membr Biol. 1995;12(1):121–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Sotgia F, Del Galdo F, Casimiro MC, Bonuccelli G, Mercier I, Whitaker-Menezes D, et al. Caveolin-1−/− null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts. Am J Pathol. 2009;174(3):746–61. doi: 10.2353/ajpath.2009.080658.PubMedCrossRefGoogle Scholar
  14. 14.
    Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol. 2009;174(6):2023–34. doi: 10.2353/ajpath.2009.080873.PubMedCrossRefGoogle Scholar
  15. 15.
    Sloan EK, Ciocca DR, Pouliot N, Natoli A, Restall C, Henderson MA, et al. Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol. 2009;174(6):2035–43. doi: 10.2353/ajpath.2009.080924.PubMedCrossRefGoogle Scholar
  16. 16.
    Witkiewicz AK, Dasgupta A, Nguyen KH, Liu C, Kovatich AJ, Schwartz GF, et al. Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer. Cancer Biol Ther. 2009;8(11):1071–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Paulsson J, Sjoblom T, Micke P, Ponten F, Landberg G, Heldin CH, et al. Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer. Am J Pathol. 2009;175(1):334–41. doi: 10.2353/ajpath.2009.081030.PubMedCrossRefGoogle Scholar
  18. 18.
    Witkiewicz AK, Casimiro MC, Dasgupta A, Mercier I, Wang C, Bonuccelli G, et al. Towards a new “stromal-based” classification system for human breast cancer prognosis and therapy. Cell Cycle. 2009;8(11):1654–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10.PubMedCrossRefGoogle Scholar
  20. 20.
    Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: a new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010;9(16):3256–76. doi: 10.4161/cc.9.16.12553.PubMedCrossRefGoogle Scholar
  21. 21.
    Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, et al. Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: a transcriptional informatics analysis with validation. Cell Cycle. 2010;9(11):2201–19.CrossRefGoogle Scholar
  22. 22.
    Migneco G, Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S, Pestell RG, et al. Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal–epithelial metabolic coupling. Cell Cycle. 2010;9(12):2412–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, et al. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle. 2010;9(12):2423–33.PubMedCrossRefGoogle Scholar
  24. 24.
    Elsheikh SE, Green AR, Rakha EA, Samaka RM, Ammar AA, Powe D, et al. Caveolin 1 and caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer. 2008;99(2):327–34. doi: 10.1038/sj.bjc.6604463.PubMedCrossRefGoogle Scholar
  25. 25.
    Pinilla SM, Honrado E, Hardisson D, Benitez J, Palacios J. Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat. 2006;99(1):85–90. doi: 10.1007/s10549-006-9184-1.PubMedCrossRefGoogle Scholar
  26. 26.
    Savage K, Lambros MB, Robertson D, Jones RL, Jones C, Mackay A, et al. Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis. Clin Cancer Res. 2007;13(1):90–101. doi: 10.1158/1078-0432.CCR-06-1371.PubMedCrossRefGoogle Scholar
  27. 27.
    Peterson TE, Guicciardi ME, Gulati R, Kleppe LS, Mueske CS, Mookadam M, et al. Caveolin-1 can regulate vascular smooth muscle cell fate by switching platelet-derived growth factor signaling from a proliferative to an apoptotic pathway. Arterioscler Thromb Vasc Biol. 2003;23(9):1521–7. doi: 10.1161/01.atv.0000081743.35125.05.PubMedCrossRefGoogle Scholar
  28. 28.
    Yamamoto M, Toya Y, Jensen RA, Ishikawa Y. Caveolin is an inhibitor of platelet-derived growth factor receptor signaling. Exp Cell Res. 1999;247(2):380–8. doi: 10.1006/excr.1998.4379.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Ja Seung Koo
    • 1
  • Seho Park
    • 2
  • Seung Il Kim
    • 2
  • Sarah Lee
    • 1
  • Byeong-Woo Park
    • 2
  1. 1.Department of PathologyYonsei University College of MedicineSeoulSouth Korea
  2. 2.Department of Surgery, Severance HospitalYonsei University College of MedicineSeoulSouth Korea

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