Skip to main content

Advertisement

Log in

Absence of caveolin-1 expression in carcinoma-associated fibroblasts of invasive micropapillary carcinoma of the breast predicts poor patient outcome

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Caveolin-1 (Cav-1) expression in stromal carcinoma-associated fibroblasts (CAFs) has been associated with tumor progression and clinical outcome. This study was undertaken to assess its prognostic significance in invasive micropapillary carcinoma of the breast (IMPC), a tumor with abundant stromal CAFs and a high tendency for nodal metastasis and poor outcome. Cav-1 expression was studied by immunohistochemistry in a group of 86 cases of IMPC along with a control group of 105 cases of invasive ductal carcinoma, not otherwise specified (IDC-NOS). Our results indicate that absence of Cav-1 expression in CAFs of IMPC is more common than in IDC-NOS (57 %, 49/86 vs. 36 %, 38/105). The absence of expression was associated with larger tumor size and higher lymph node stage (P < 0.05) of IMPC. Univariate analysis suggested absence of Cav-1 in CAFs to be a candidate independent predictor of reduced progression-free survival (PFS) (HR = 3.945, 95 % CI = 1.717–9.063, P = 0.001), which was confirmed by multivariable analysis (P = 0.018). In patients with IMPC spreading to local lymph nodes, loss of stromal Cav-1 predicted a fourfold increase in risk for shortened PFS. In contrast, no significant difference of tumor epithelial Cav-1 expression was found between IMPC and IDC-NOS, and the expression of tumor Cav-1 was not significantly associated with the prognosis of patients with IMPC. Absence of Cav-1 expression in CAFs is a strong prognostic factor for IMPC patients, and it may further subgroup the patients with lymph node metastasis to guide clinical management.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Schauer IG, Sood AK, Mok S et al (2011) Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. Neoplasia 13:393–405

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Xing F, Saidou J, Watabe K (2010) Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci 15:166–179

    Article  CAS  Google Scholar 

  3. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB et al (2010) 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 9:3256–3276

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Guido C, Whitaker-Menezes D, Capparelli C et al (2012) Metabolic reprogramming of cancer-associated fibroblasts by TGF-beta drives tumor growth: connecting TGF-beta signaling with "Warburg-like" cancer metabolism and L-lactate production. Cell Cycle 11:3019–3035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Pavlides S, Tsirigos A, Vera I et al (2010) 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 9:2201–2219

    Article  CAS  PubMed  Google Scholar 

  6. Sotgia F, Martinez-Outschoorn UE, Howell A et al (2012) Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 7:423–467

    Article  CAS  PubMed  Google Scholar 

  7. Park SS, Kim JE, Kim YA et al (2005) Caveolin-1 is down-regulated and inversely correlated with HER2 and EGFR expression status in invasive ductal carcinoma of the breast. Histopathology 47:625–630

    Article  PubMed  Google Scholar 

  8. Mercier I, Casimiro MC, Wang C et al (2008) 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 7:1212–1225

    Article  CAS  PubMed  Google Scholar 

  9. Sloan EK, Ciocca DR, Pouliot N et al (2009) Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol 174:2035–2043

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Witkiewicz AK, Dasgupta A, Sotgia F et al (2009) An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 174:2023–2034

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Witkiewicz AK, Dasgupta A, Sammons S et al (2010) Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers. Cancer Biol Ther 10:135–143

    Article  PubMed Central  PubMed  Google Scholar 

  12. El-Gendi SM, Mostafa MF, El-Gendi AM (2012) Stromal caveolin-1 expression in breast carcinoma. Correlation with early tumor recurrence and clinical outcome. Pathol Oncol Res 18:459–469

    Article  CAS  PubMed  Google Scholar 

  13. Simpkins SA, Hanby AM, Holliday DL et al (2012) Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J Pathol 227:490–498

    Article  CAS  PubMed  Google Scholar 

  14. Zekioglu O, Erhan Y, Ciris M et al (2004) Invasive micropapillary carcinoma of the breast: high incidence of lymph node metastasis with extranodal extension and its immunohistochemical profile compared with invasive ductal carcinoma. Histopathology 44:18–23

    Article  CAS  PubMed  Google Scholar 

  15. Walsh MM, Bleiweiss IJ (2001) Invasive micropapillary carcinoma of the breast: eighty cases of an underrecognized entity. Hum Pathol 32:583–589

    Article  CAS  PubMed  Google Scholar 

  16. Fu L, Ikuo M, Fu XY et al (2004) Relationship between biologic behavior and morphologic features of invasive micropapillary carcinoma of the breast. Zhonghua Bing Li Xue Za Zhi 33:21–25

    PubMed  Google Scholar 

  17. Reis-Filho JS, Ellis IO (2012) WHO classification of tumours of the breast. IARC, Lyon

    Google Scholar 

  18. Hammond ME, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795

    Article  PubMed Central  PubMed  Google Scholar 

  19. Cantiani L, Manara MC, Zucchini C et al (2007) Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling. Cancer Res 67:7675–7685

    Article  CAS  PubMed  Google Scholar 

  20. Wikman H, Kettunen E, Seppanen JK et al (2002) Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array. Oncogene 21:5804–5813

    Article  CAS  PubMed  Google Scholar 

  21. Kato K, Hida Y, Miyamoto M et al (2002) Overexpression of caveolin-1 in esophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Cancer 94:929–933

    Article  CAS  PubMed  Google Scholar 

  22. Nam KH, Lee BL, Park JH et al (2013) Caveolin 1 expression correlates with poor prognosis and focal adhesion kinase expression in gastric cancer. Pathobiology 80:87–94

    Article  CAS  PubMed  Google Scholar 

  23. Liu P, Rudick M, Anderson RG (2002) Multiple functions of caveolin-1. J Biol Chem 277:41295–41298

    Article  CAS  PubMed  Google Scholar 

  24. Liu F, Lang R, Wei J et al (2009) Increased expression of SDF-1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast. Histopathology 54:741–750

    Article  PubMed  Google Scholar 

  25. Li W, Liu F, Lei T et al (2010) The clinicopathological significance of CD44+/CD24−/low and CD24+ tumor cells in invasive micropapillary carcinoma of the breast. Pathol Res Pract 206:828–834

    Article  CAS  PubMed  Google Scholar 

  26. Elsheikh SE, Green AR, Rakha EA et al (2008) Caveolin 1 and caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer 99:327–334

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Li T, Sotgia F, Vuolo MA et al (2006) Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status. Am J Pathol 168:1998–2013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Di Vizio D, Morello M, Sotgia F et al (2009) An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation. Cell Cycle 8:2420–2424

    Article  PubMed Central  PubMed  Google Scholar 

  29. Jia Y, Wang N, Wang J et al (2014) Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: a potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis. Ann Surg Oncol 21:329–336

    Article  PubMed  Google Scholar 

  30. Pavlides S, Tsirigos A, Migneco G et al (2010) The autophagic tumor stroma model of cancer: role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle 9:3485–3505

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Salem AF, Whitaker-Menezes D, Lin Z et al (2012) Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. Cell Cycle 11:2545–2556

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Sotgia F, Martinez-Outschoorn UE, Pavlides S et al (2011) Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 13:213

    Article  PubMed Central  PubMed  Google Scholar 

  33. Sanchez-Alvarez R, Martinez-Outschoorn UE, Lin Z et al (2013) Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention. Cell Cycle 12:289–301

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Senetta R, Stella G, Pozzi E et al (2013) Caveolin-1 as a promoter of tumour spreading: when, how, where and why. J Cell Mol Med 17:325–336

    Article  CAS  PubMed  Google Scholar 

  35. Goetz JG, Minguet S, Navarro-Lerida I et al (2011) Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146:148–163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Ayala G, Morello M, Frolov A et al (2013) Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression. J Pathol 231:77–87

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Xia H, Khalil W, Kahm J et al (2010) Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. Am J Pathol 176:2626–2637

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bodmer M, Meier C, Krahenbuhl S et al (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33:1304–1308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by National Natural Science Foundation of China (Grant No. 30930038, No. 81202101 and No. 81302292) and Innovation Funding for graduate of Tianjin Medical University, third phase of the 211 Project for Higher Education (Grant No. 2010GSI07).

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Li Fu.

Additional information

M. Ren and F. Liu contributed equally to this study and should be regarded as joint first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ren, M., Liu, F., Zhu, Y. et al. Absence of caveolin-1 expression in carcinoma-associated fibroblasts of invasive micropapillary carcinoma of the breast predicts poor patient outcome. Virchows Arch 465, 291–298 (2014). https://doi.org/10.1007/s00428-014-1614-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1614-6

Keywords

Navigation