Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer
The role of caveolin 1 (CAV1), a structural component of caveolae in breast cancer is controversial, although most studies suggest that it functions as a tumor-suppressor gene. In addition, some studies have identified CAV1 as a marker of myoepithelial cells. Since myoepithelial markers are frequently expressed in breast carcinomas with a basal-like phenotype, which are frequently occurring tumors in women with BRCA1 germline mutations, we evaluated whether CAV1 was associated with a basal-like phenotype in 509 sporadic and 47 hereditary BRCA1-/BRCA2-associated carcinomas. Immunohistochemistry was performed on tissue microarrays and cases were classified as having a basal-like-phenotype if they were estrogen-receptor- and HER2-negative but cytokeratin 5/6- and/or epidermal growth factor receptor-positive. In sporadic carcinomas, CAV1 expression was found in 21 out of 496 valuable cases (4.2%). A basal-like-phenotype was found in 53 out of 498 (10.6%) cases. A strong association was found between CAV1 expression and a basal-like-phenotype, since 52% of tumors that expressed CAV1 had this phenotype, compared with only 9% of CAV1-negative carcinomas (p<0.001). CAV1 was expressed in six (12.8%) familial cases, five of which had a basal-like-phenotype (p = 0.009). Moreover, these six CAV1-positive cases were BRCA1 tumors. The difference in the frequency of CAV1 expression between BRCA1- and BRCA2-associated tumors was statistically significant (p = 0.024). In conclusion, this study reports for the first time CAV1 expression in BRCA1 and BRCA2 hereditary breast cancer and identifies CAV1 as a marker associated with a basal-like-phenotype in both hereditary and sporadic breast cancer.
Keywordsbasal-like phenotype breast cancer caveolin tissue-microarray
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The authors thank the CNIO Immunohistochemical Unit for expert technical assistance.
This study was supported by the Spanish Ministry of Education and Science (SAF2004-08258-C02-01) and Instituto de Salud Carlos III (PI051890). Socorro María Rodríguez-Pinilla is recipient of a research grant from the Fondo de Investigación Sanitaria, Spain, and Emiliano Honrado is funded by the Foundation of the Spanish Association against cancer (AECC).
- 4.Tso CL, McBride WH, Sun J, Patel B, Tsui KH, Paik SH, Gitlitz B, Caliliw R, van Ophoven A, Wu L, deKernion J, Belldegrun A. (2000) Androgen deprivation induces selective outgrowth of aggressive hormone-refractory prostate cancer clones expressing distinct cellular and molecular properties not present in parental androgen-dependent cancer cells Cancer J 6:220–233PubMedGoogle Scholar
- 6.Hu YC, Lam KY, Law S, Wong J, Srivastava G. (2001) Profiling of differentially expressed cancer-related genes in esophageal squamous cell carcinoma (ESCC) using human cancer c DNA arrays: overexpression of oncogene MET correlates with tumor differentiation in ESCC Clin Cancer Res 7:3519–3525PubMedGoogle Scholar
- 10.Sakamoto M, Kondo A, Kawasaki K, Goto T, Sakamoto H, Miyake K, Koyamatsu Y, Akiya T, Iwabuchi H, Muroya T, Ochiai K, Tanaka T, Kikuchi Y, Tenjin Y. (2001) Analysis of gene expression profiles associated with cisplatin resistance in human ovarian cancer cell lines and tissues using cDNA microarray Hum Cell 14:305–315:PubMedGoogle Scholar
- 17.Williams TM, Medina F, Badano I, Hazan RB, Hutchinson J, Muller WJ, Chopra NG, Scherer PE, Pestell RG, Lisanti MP. (2004) Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo. Role of cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion J Biol Chem 279:51630–51646PubMedCrossRefGoogle Scholar
- 21.Van den Eynden GG, Laere SJV, Van der Auwera I, Merajver SD, Van Marck EA, van Dam P, Vermeulen PB, Dirix LY, van Golen KL. (2005) Overexpression of caveolin-1 and -2 in cell lines and in human simples of inflammatory breast cancer Breast Cancer Res Treat 22:1–10Google Scholar
- 22.Jones C, Mackay A, Grigoriadis A, Cossu A, Reis-Filho JS, Fulford L, Dexter T, Davies S, Bulmer K, Ford E, Parry S, Budroni M, Palmieri G, Neville AM, O’Hare MJ, Lakhani SR. (2004) Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer Cancer Res 64:3037–3045PubMedCrossRefGoogle Scholar
- 23.Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. (2000) Molecular portraits of human breast tumours Nature 406:747–752PubMedCrossRefGoogle Scholar
- 26.Jacquemier J, Padovani L, Rabayrol L, Lakhani SR, Penault-Llorca F, Denoux Y, Fiche M, Figueiro P, Maisougrosse V, Ledonssal V, Martinez Penuela J, Vdvarhely N, El Makdissi G, Ginestier C, Geneix J, Charafe-Jauffret E, Xerri L, Eisinger F, Birnbaum D, Sobol H. (2005) Typical medullary breast carcinomas have a basal/myoepithelial phenotype J Pathol 207:260–268PubMedCrossRefGoogle Scholar
- 28.Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matesse JC, Brown PO, Botstein D, Eystein-Lonning P, Borresen- Dale AL. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications Proc Natl Acad Sci USA 98:10869–10874PubMedCrossRefGoogle Scholar
- 29.Van’t Veer LJ, Dal H, van de Vijver MJ, He YD, Hart AA, Mao M, Meterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. (2002) Gene expression profiling predicts clinical outcome of breast cancer Nature 415:530–535CrossRefGoogle Scholar
- 30.Rouzier N, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L. (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy Clin Cancer Res 11:5678–5685PubMedCrossRefGoogle Scholar
- 31.Rodríguez-Pinilla SM, Sarrió D, Honrado E, Hardisson D, Calero F, Benitez J, Palacios J: Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res, 12: 2006Google Scholar
- 32.Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeler J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets Proc Natl Acad Sci USA 100:8418–8423PubMedCrossRefGoogle Scholar
- 33.Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, Bishop T, Benitez J, Rivas C, Bignon YJ, Chang-Claude J, Hamann U, Cornelisse CJ, Devilee P, Beckmann MW, Nestle-Kramling C, Daly PA, Haites N, Varley J, Lalloo F, Evans G, Maugard C, Meijers-Heijboer H, Klijn JG, Olah E, Gusterson BA, Pilotti S, Radice P, Scherneck S, Sobol H, Jacquemier J, Wagner T, Peto J, Stratton MR, McGuffong L, Easton DF. (2005) Breast Cancer linkage consortium. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype Clin Cancer Res 11:5175–5180PubMedCrossRefGoogle Scholar
- 34.Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM. (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma Clin Cancer Res 10:5367–5374PubMedCrossRefGoogle Scholar
- 35.Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, Rodríguez S, Cigudosa JC, Diez O, Alonso C, Lerma E, Dopazo J, Rivas C, Benitez J. (2005) Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers Breast Cancer Res Treat 90:5–14PubMedCrossRefGoogle Scholar
- 38.Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adélaïde J, Cervera N, Fekairi S, Xerri L, Jacquemier J, Birnbaum D, Bertucci F: Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 24: 1–12, 2005Google Scholar
- 42.Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, Begin LR, Hamel N, Goffin JR, Wong N, Trudel M, Kapusta L, Porter P, Akslen LA. (2004) The prognostic implication of the basal-like (cyclin-E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancers Cancer Res 64:830–835PubMedCrossRefGoogle Scholar
- 44.Palacios J, Honrado E, Osorio A, Diez O, Rivas C, Benitez J: Re: Germline mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 96: 712–714, 2004Google Scholar