title: Nuclear HER3 is associated with favorable overall survival in uveal melanoma.
abstract: HER3 is a member of the epidermal growth factor receptor (EGFR) family and is expressed in several types of cancer. Both the cytoplasmic and nuclear appearances of the receptor have been reported. Here, we investigate the expression and subcellular distribution of HER3 in uveal melanoma (UM) cells and tissues and its potential impact on clinical outcome of patients. Paraffin-embedded samples from 128 consecutive UM patients, enucleated without alternative treatment on UM diagnosis, were evaluated for HER3 using immunohistochemistry. Immunoreactivity was scored for frequency, intensity of positive cells, and subcellular distribution. The results were correlated with the established clinicopathological parameters using univariate and multivariate statistical analyses. HER3 expression was shown in 70% of the cases (89/128). This contrasts with the other EGFR family receptors (EGFR, HER2 and HER4) that are infrequently expressed in UM. Surprisingly, HER3 was found to be localized solely in the cell nuclei in 56 cases. The remaining 33 HER3 positive cases showed diffuse distribution (cytoplasmic ± nuclear). Nuclear HER3 was independently correlated with a more favorable overall survival (p = 0.043 and hazard ratio = 0.618) compared to cases with diffuse and/or no HER3. Nuclear localization of HER3 was also confirmed in fresh UM material and in UM cell lines. In conclusion, HER3 is frequently localized solely in the cell nuclei in UM and as such it predicts a more favorable overall survival.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Trocmé
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
authors.forename: C Christian
authors.initials: CC
authors.lastname: Johansson
authors.forename: Charlotta
authors.initials: C
authors.lastname: All-Eriksson
authors.forename: Mario A
authors.initials: MA
authors.lastname: Economou
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Seregard
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D020893:Receptor, ErbB-3 / Q000096:biosynthesis*; D066247:Receptor, ErbB-4; D016019:Survival Analysis; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000401:mortality; D000098943:Uveal Melanoma
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human