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A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear β-catenin immunoreactivity, independent of EGFR and HER-2 gene amplification or expression

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Abstract

Nuclear translocation of β-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in nonsmall cell lung cancer. Less is known on β-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of β-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or β-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). β-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for β-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. β-catenin was expressed in all 96 high-grade neuroendocrine tumors, the vast majority (94%) showing >50% immunopositive cells. A disarrayed immunoreactivity, however, was commonly encountered consisting in variably altered membrane-associated patterns of staining along with progressive accumulation of cytoplasmic immunoreactivity. In LCNEC, but not in SCLC, the disarrayed patterns correlated with EGFR and HER-2 protein expression. β-catenin nuclear accumulation was found in nine tumors, including seven LCNEC and two SCLC, and was always associated with disarrayed immunoreactivity and increased MMP-7, but not cyclin D1 expression. These cases, however, did not show β-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear β-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of β-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows β-catenin nuclear accumulation in association with increased expression of MMP-7, but not of cyclin D1, independent of EGFR and HER-2 gene amplification or expression.

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Acknowledgements

This study was supported by Associazione Italiana Ricerca Cancro (AIRC), Fondazione Cassa di Risparmio di Verona (Bando 2001), CNR “Diagnostica molecolare in oncologia” and MIUR, Rome, Italy.

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Authors and Affiliations

  1. Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy

    Giuseppe Pelosi, Barbara Del Curto, Angelica Sonzogni, Michele Masullo & Giuseppe Viale

  2. Department of Pathology, University of Verona, Verona, Italy

    Aldo Scarpa & Patrick S. Moore

  3. Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy

    Giulia Veronesi & Lorenzo Spaggiari

  4. Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

    Patrick Maisonneuve

  5. Divisione di Anatomia Patologica e Medicina di Laboratorio, Istituto Europeo di Oncologia, Via G. Ripamonti, 435, I-20141, Milano, Italy

    Giuseppe Pelosi

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  1. Giuseppe Pelosi
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Pelosi, G., Scarpa, A., Veronesi, G. et al. A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear β-catenin immunoreactivity, independent of EGFR and HER-2 gene amplification or expression. Virchows Arch 447, 969–977 (2005). https://doi.org/10.1007/s00428-005-0044-x

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