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Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Abstract

Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial–mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-a-genome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.

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References

  • Al Sayed AD, El Weshi AN, Tulbah AM, Rahal MM, Ezzat AA . (2006). Metaplastic carcinoma of the breast clinical presentation, treatment results and prognostic factors. Acta Oncol 45: 188–195.

    Article  Google Scholar 

  • Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. (2000). Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29.

    Article  CAS  Google Scholar 

  • Barnes PJ, Boutilier R, Chiasson D, Rayson D . (2005). Metaplastic breast carcinoma: clinical-pathologic characteristics and HER2/neu expression. Breast Cancer Res Treat 91: 173–178.

    Article  CAS  Google Scholar 

  • Bilanges B, Varrault A, Basyuk E, Rodriguez C, Mazumdar A, Pantaloni C et al. (1999). Loss of expression of the candidate tumor suppressor gene ZAC in breast cancer cell lines and primary tumors. Oncogene 18: 3979–3988.

    Article  CAS  Google Scholar 

  • Bundy LM, Sealy L . (2003). CCAAT/enhancer binding protein beta (C/EBPbeta)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture. Oncogene 22: 869–883.

    Article  CAS  Google Scholar 

  • Carter MR, Hornick JL, Lester S, Fletcher CD . (2006). Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg Pathol 30: 300–309.

    Article  Google Scholar 

  • Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C et al. (2006). An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 25: 3994–4008.

    Article  CAS  Google Scholar 

  • Doege KJ, Sasaki M, Kimura T, Yamada Y . (1991). Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms. J Biol Chem 266: 894–902.

    CAS  PubMed  Google Scholar 

  • Framson PE, Sage EH . (2004). SPARC and tumor growth: where the seed meets the soil? J Cell Biochem 92: 679–690.

    Article  CAS  Google Scholar 

  • Fujiwara S, Takeo N, Otani Y, Parry DA, Kunimatsu M, Lu R et al. (2001). Epiplakin, a novel member of the Plakin family originally identified as a 450-kDa human epidermal autoantigen. Structure and tissue localization. J Biol Chem 276: 13340–13347.

    Article  CAS  Google Scholar 

  • Gersch RP, Lombardo F, McGovern SC, Hadjiargyrou M . (2005). Reactivation of Hox gene expression during bone regeneration. J Orthop Res 23: 882–890.

    Article  CAS  Google Scholar 

  • Jansen S, Stefan C, Creemers JW, Waelkens E, Van Eynde A, Stalmans W et al. (2005). Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. J Cell Sci 118: 3081–3089.

    Article  CAS  Google Scholar 

  • Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P et al. (2006). Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116: 1561–1570.

    Article  CAS  Google Scholar 

  • Jones C, Mackay A, Grigoriadis A, Cossu A, Reis-Filho JS, Fulford L 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: 3037–3045.

    Article  CAS  Google Scholar 

  • Korsching E, Packeisen J, Liedtke C, Hungermann D, Wulfing P, van Diest PJ et al. (2005). The origin of vimentin expression in invasive breast cancer: epithelial–mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 206: 451–457.

    Article  CAS  Google Scholar 

  • Kusafuka K, Ishiwata T, Sugisaki Y, Takemura T, Kusafuka M, Hisha H et al. (2004). Lumican expression is associated with the formation of mesenchyme-like elements in salivary pleomorphic adenomas. J Pathol 203: 953–960.

    Article  CAS  Google Scholar 

  • Lee JM, Dedhar S, Kalluri R, Thompson EW . (2006). The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172: 973–981.

    Article  CAS  Google Scholar 

  • Lemmers C, Michel D, Lane-Guermonprez L, Delgrossi MH, Medina E, Arsanto JP et al. (2004). CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol Biol Cell 15: 1324–1333.

    Article  CAS  Google Scholar 

  • Lien HC, Lin CW, Mao TL, Kuo SH, Hsiao CH, Huang CS . (2004). p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components. J Pathol 204: 131–139.

    Article  CAS  Google Scholar 

  • Liu Y, Nusrat A, Schnell FJ, Reaves TA, Walsh S, Pochet M et al. (2000). Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci 113: 2363–2374.

    CAS  PubMed  Google Scholar 

  • Ma L, Lu MF, Schwartz RJ, Martin JF . (2005). Bmp2 is essential for cardiac cushion epithelial–mesenchymal transition and myocardial patterning. Development 132: 5601–5611.

    Article  CAS  Google Scholar 

  • Oehler MK, Fischer DC, Orlowska-Volk M, Herrle F, Kieback DG, Rees MC et al. (2003). Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer. Br J Cancer 89: 1927–1933.

    Article  CAS  Google Scholar 

  • Pezzi CM, Patel-Parekh L, Cole K, Franko J, Klimberg VS, Bland K . (2007). Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the national cancer data base. Ann Surg Oncol 14: 166–173.

    Article  Google Scholar 

  • Pfister BE, Aydelotte MB, Burkhart W, Kuettner KE, Schmid TM . (2001). Del1: a new protein in the superficial layer of articular cartilage. Biochem Biophys Res Commun 286: 268–273.

    Article  CAS  Google Scholar 

  • Reinholz MM, Iturria SJ, Ingle JN, Roche PC . (2002). Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat 74: 255–269.

    Article  CAS  Google Scholar 

  • Reis-Filho JS, Milanezi F, Paredes J, Silva P, Pereira EM, Maeda SA et al. (2003). Novel and classic myoepithelial/stem cell markers in metaplastic carcinomas of the breast. Appl Immunohistochem Mol Morphol 11: 1–8.

    CAS  PubMed  Google Scholar 

  • Rosai J . (2004). Rosai and Ackerman's Surgical Pathology. St Louis: Mosby, pp 1828–1829.

    Google Scholar 

  • Ryoo HM, Lee MH, Kim YJ . (2006). Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells. Gene 366: 51–57.

    Article  CAS  Google Scholar 

  • Saika S, Miyamoto T, Tanaka S, Tanaka T, Ishida I, Ohnishi Y et al. (2003). Response of lens epithelial cells to injury: role of lumican in epithelial–mesenchymal transition. Invest Ophthalmol Vis Sci 44: 2094–2102.

    Article  Google Scholar 

  • Siddiq F, Sarkar FH, Wali A, Pass HI, Lonardo F . (2004). Increased osteonectin expression is associated with malignant transformation and tumor associated fibrosis in the lung. Lung Cancer 45: 197–205.

    Article  Google Scholar 

  • Soda H, Raymond E, Sharma S, Lawrence R, Cerna C, Gomez L et al. (1998). Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units. Anticancer Drugs 9: 327–331.

    Article  CAS  Google Scholar 

  • Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT et al. (2005). ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648–652.

    Article  CAS  Google Scholar 

  • Thiery JP . (2002). Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    Article  CAS  Google Scholar 

  • Wilson CA, Dering J . (2004). Recent translational research: microarray expression profiling of breast cancer – beyond classification and prognostic markers? Breast Cancer Res 6: 192–200.

    Article  CAS  Google Scholar 

  • Xu X, Bringas Jr P, Soriano P, Chai Y . (2005). PDGFR-alpha signaling is critical for tooth cusp and palate morphogenesis. Dev Dyn 232: 75–84.

    Article  CAS  Google Scholar 

  • Zavadil J, Bottinger EP . (2005). TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24: 5764–5774.

    Article  CAS  Google Scholar 

  • Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M et al. (2004). Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat Cell Biol 6: 931–940.

    Article  CAS  Google Scholar 

  • Zhuang Z, Lininger RA, Man YG, Albuquerque A, Merino MJ, Tavassoli FA . (1997). Identical clonality of both components of mammary carcinosarcoma with differential loss of heterozygosity. Mod Pathol 10: 354–362.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by National Science Council Grant NSC 94-2320-B-002-057 (HCL), Grant NSC 95-2314-B002-012 (KJC) and Grant NSC 94-2314-B-002-118 (FJH).

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Correspondence to K J Chang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lien, H., Hsiao, Y., Lin, Y. et al. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition. Oncogene 26, 7859–7871 (2007). https://doi.org/10.1038/sj.onc.1210593

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