title: A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear beta-catenin immunoreactivity, independent of EGFR and HER-2 gene amplification or expression.
abstract: Nuclear translocation of beta-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in non-small cell lung cancer. Less is known on beta-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of beta-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or beta-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). beta-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for beta-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. beta-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. beta-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 beta-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear beta-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of beta-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows beta-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.
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Giulia
authors.initials: G
authors.lastname: Veronesi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spaggiari
authors.forename: Barbara
authors.initials: B
authors.lastname: Del Curto
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Angelica
authors.initials: A
authors.lastname: Sonzogni
authors.forename: Michele
authors.initials: M
authors.lastname: Masullo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis*; D008875:Middle Aged; D020893:Receptor, ErbB-3 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D020783:Matrix Metalloproteinase 7