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01-07-2008 | Preclinical Study

Distribution and significance of caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis

Authors: Kay Savage, Samuel Leung, S. Katrina Todd, Lindsay A. Brown, Robin L. Jones, David Robertson, Michelle James, Suzanne Parry, S. Maria Rodrigues Pinilla, David Huntsman, Jorge S. Reis-Filho

Published in: Breast Cancer Research and Treatment | Issue 2/2008

Abstract

Background

The aims of this study were to define the distribution of caveolin 2 (CAV2) in frozen and formalin fixed, paraffin embedded (FFPE) normal breast samples and the significance of CAV2 expression in breast cancer.

Methods

Caveolin 2 distribution in frozen and paraffin-embedded whole tissue sections of normal breast was evaluated using immunohistochemistry and immunofluorescence, in conjunction with antibodies to define luminal epithelial cells (oestrogen receptor and cytokeratin 8/18) and myoepithelial/ basal cells (cytokeratins 14 and 5/6, p63 and smooth muscle actin). CAV2 expression was also immunohistochemically analysed in two independent cohorts of invasive breast carcinomas (n = 245 and n = 418).

Results

In normal breast, CAV2 was expressed in myoepithelial cells, endothelial cells, fibroblasts and adipocytes. Luminal epithelial cells showed no or only negligible staining. CAV2 expression was observed in 9.6% of all breast cancers and was strongly correlated with high histological grade, lack of oestrogen receptor, progesterone receptor and cyclin D1 expression, and positivity for epidermal growth factor receptor, basal markers, p53 expression, and high proliferation index. Furthermore, CAV2 expression was significantly associated with basal-like immunophenotype and proved to be a prognostic factor for breast cancer-specific survival on univariate analysis.

Conclusion

Our results demonstrate that CAV2 is preferentially expressed in basal-like cancers and is associated with poor prognosis. Further in vitro studies are required to determine whether CAV2 has oncogenic properties or is only a surrogate marker of basal-like carcinomas.

Engelman JA, Zhang XL, Lisanti MP (1998) Genes encoding human caveolin-1 and -2 are co-localized to the D7S522 locus (7q31.1), a known fragile site (FRA7G) that is frequently deleted in human cancers. FEBS Lett 436:403–410PubMedCrossRef

Scherer PE, Okamoto T, Chun M et al (1996) Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci U S A 93:131–135PubMedCrossRef

Hnasko R, Lisanti MP (2003) The biology of caveolae: lessons from caveolin knockout mice and implications for human disease. Mol Interv 3:445–464PubMedCrossRef

Stan RV (2005) Structure of caveolae. Biochim Biophys Acta 1746:334–348PubMedCrossRef

Bouras T, Lisanti MP, Pestell RG (2004) Caveolin-1 in breast cancer. Cancer Biol Ther 3:931–941PubMedCrossRef

Savage K, Lambros MB, Robertson D et al (2007) 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 13:90–101PubMedCrossRef

Williams TM, Lisanti MP (2005) Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol 288:C494–C506PubMedCrossRef

Razani B, Schlegel A, Liu J et al (2001) Caveolin-1, a putative tumour suppressor gene. Biochem Soc Trans 29:494–499PubMedCrossRef

Scherer PE, Lewis RY, Volonte D et al (1997) Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo. J Biol Chem 272:29337–29346PubMedCrossRef

10.

Le Lay S, Kurzchalia TV (2005) Getting rid of caveolins: phenotypes of caveolin-deficient animals. Biochim Biophys Acta 1746:322–333PubMedCrossRef

11.

Razani B, Wang XB, Engelman JA et al (2002) Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae. Mol Cell Biol 22:2329–2344PubMedCrossRef

12.

Couet J, Li S, Okamoto T et al (1997) Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem 272:6525–6533PubMedCrossRef

13.

Couet J, Sargiacomo M, Lisanti MP (1997) Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem 272:30429–30438PubMedCrossRef

14.

Charafe-Jauffret E, Ginestier C, Monville F et al (2005) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25:2273–2284CrossRef

15.

Chen ST, Lin SY, Yeh KT et al (2004) Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers. Int J Mol Med 14:577–582PubMed

16.

Engelman JA, Zhang XL, Lisanti MP (1999) Sequence and detailed organization of the human caveolin-1 and -2 genes located near the D7S522 locus (7q31.1). Methylation of a CpG island in the 5′ promoter region of the caveolin-1 gene in human breast cancer cell lines. FEBS Lett 448:221–230PubMedCrossRef

17.

Hurlstone AF, Reid G, Reeves JR et al (1999) Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines. Oncogene 18:1881–1890PubMedCrossRef

18.

Pinilla SM, Honrado E, Hardisson D et al (2006) Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat 99:85–90PubMedCrossRef

19.

Hayashi K, Matsuda S, Machida K et al (2001) Invasion activating caveolin-1 mutation in human scirrhous breast cancers. Cancer Res 61:2361–2364PubMed

20.

Jones C, Mackay A, Grigoriadis A et al (2004) Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer. Cancer Res 64:3037–3045PubMedCrossRef

21.

Lee H, Park DS, Razani B et al (2002) Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (−/−) null mice show mammary epithelial cell hyperplasia. Am J Pathol 161:1357–1369PubMed

22.

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 47:625–630PubMedCrossRef

23.

Sagara Y, Mimori K, Yoshinaga K et al (2004) Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer. Br J Cancer 91:959–965PubMed

24.

Van den Eynden GG, Van Laere SJ, Van der Auwera I et al (2006) Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer. Breast Cancer Res Treat 95:219–228PubMedCrossRef

25.

Yang G, Truong LD, Timme TL et al (1998) Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res 4:1873–1880PubMed

26.

Jacquemier J, Padovani L, Rabayrol L et al (2005) Typical medullary breast carcinomas have a basal/myoepithelial phenotype. J Pathol 207:260–268PubMedCrossRef

27.

Sotgia F, Rui H, Bonuccelli G et al (2006) Caveolin-1, mammary stem cells, and estrogen-dependent breast cancers. Cancer Res 66:10647–10651PubMedCrossRef

28.

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 168:1998–2013PubMedCrossRef

29.

Chin K, DeVries S, Fridlyand J et al (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10:529–541PubMedCrossRef

30.

Neve RM, Chin K, Fridlyand J et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527PubMedCrossRef

31.

Van Laere S, Van der Auwera I, Van den Eynden GG et al (2005) Distinct molecular signature of inflammatory breast cancer by cDNA microarray analysis. Breast Cancer Res Treat 93:237–246PubMedCrossRef

32.

Reis-Filho JS, Savage K, Lambros MB et al (2006) Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod Pathol 19:999–1009PubMedCrossRef

33.

Makretsov NA, Huntsman DG, Nielsen TO et al (2004) Hierarchical clustering analysis of tissue microarray immunostaining data identifies prognostically significant groups of breast carcinoma. Clin Cancer Res 10:6143–6151PubMedCrossRef

34.

Prentice LM, Shadeo A, Lestou VS et al (2005) NRG1 gene rearrangements in clinical breast cancer: identification of an adjacent novel amplicon associated with poor prognosis. Oncogene 24:7281–7289PubMedCrossRef

35.

Elston CW, Ellis IO (1991) 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 19:403–410PubMedCrossRef

36.

Singletary SE, Connolly JL (2006) Breast cancer staging: working with the sixth edition of the AJCC Cancer Staging Manual. CA Cancer J Clin 56:37–47; quiz 50–1PubMedCrossRef

37.

Nielsen TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374PubMedCrossRef

38.

Tischkowitz M, Brunet JS, Begin LR et al (2007) Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 7(1):134PubMedCrossRef

39.

Brown LA, Irving J, Parker R et al (2006) Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol Oncol 100:264–270PubMedCrossRef

40.

Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef

41.

Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874PubMedCrossRef

42.

Miller LD, Smeds J, George J et al (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A 102:13550–13555PubMedCrossRef

43.

Pawitan Y, Bjohle J, Amler L et al (2005) Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res 7:R953–R964PubMedCrossRef

44.

Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25:5846–5853PubMedCrossRef

45.

Pike LJ (2005) Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta 1746:260–273PubMedCrossRef

46.

Abulrob A, Giuseppin S, Andrade MF et al (2004) Interactions of EGFR and caveolin-1 in human glioblastoma cells: evidence that tyrosine phosphorylation regulates EGFR association with caveolae. Oncogene 23:6967–6979PubMedCrossRef

47.

Ringerike T, Blystad FD, Levy FO et al (2002) Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae. J Cell Sci 115:1331–1340PubMed

48.

Razandi M, Oh P, Pedram A et al (2002) ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol Endocrinol 16:100–115PubMedCrossRef

49.

Kiss AL, Turi A, Mullner N et al (2005) Oestrogen-mediated tyrosine phosphorylation of caveolin-1 and its effect on the oestrogen receptor localisation: an in vivo study. Mol Cell Endocrinol 245:128–137PubMedCrossRef

50.

Yang FL, He H, Liu XX et al (2006) Effects of raloxifene on caveolin-1 mRNA and protein expressions in vascular smooth muscle cells. Acta Biochim Biophys Sin (Shanghai) 38:747–752CrossRef

51.

Van Laere SJ, Van den Eynden GG, Van der Auwera I et al (2006) Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling. Breast Cancer Res Treat 95:243–255PubMedCrossRef

52.

Vekris A, Meynard D, Haaz MC et al (2004) Molecular determinants of the cytotoxicity of platinum compounds: the contribution of in silico research. Cancer Res 64:356–362PubMedCrossRef

53.

Huang F, Reeves K, Han X et al (2007) Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res 67:2226–2238PubMedCrossRef

54.

Brown MT, Cooper JA (1996) Regulation, substrates and functions of src. Biochim Biophys Acta 1287:121–149PubMed

Title: Distribution and significance of caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis
Authors: Kay Savage
Samuel Leung
S. Katrina Todd
Lindsay A. Brown
Robin L. Jones
David Robertson
Michelle James
Suzanne Parry
S. Maria Rodrigues Pinilla
David Huntsman
Jorge S. Reis-Filho
Publication date: 01-07-2008
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-007-9718-1

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Abstract

Background

Methods

Results

Conclusion

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