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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


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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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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Correspondence to 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).

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  • Lung
  • Neuroendocrine carcinoma
  • β-catenin
  • EGFR
  • MMP-7