Open AccessIntegrated and Functional Genomics Analysis Validates the Relevance of the Nuclear Variant ErbB380kDa in Prostate Cancer Progression
Author(s) -
Mahmoud El Maassarani,
Alice Barbarin,
Gaëlle Fromont,
Ouafae Kaissi,
Margot Lebbe,
Brigitte Vannier,
Ahmed Moussa,
Paule Séité
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0155950
Subject(s) - prostate cancer , biology , cancer research , cancer , receptor tyrosine kinase , nuclear receptor , erbb , cancer cell , nuclear localization sequence , prostate , signal transduction , microbiology and biotechnology , gene , genetics , cytoplasm , transcription factor
The EGF-family of tyrosine-kinase receptors activates cytoplasmic pathways involved in cell proliferation, migration and differentiation in response to specific extracellular ligands. Beside these canonical pathways, the nuclear localization of the ErbB receptors in primary tumours and cancer cell lines led to investigate their role as transcriptional regulators of cancer genes. The nuclear localization of ErbB3 has been reported in various cancer tissues and cell lines but the nuclear functions and the putative correlation with tumour progression and resistance to therapy remain unclear. We first assessed ErbB3 expression in normal and tumour prostate tissues. The nuclear staining was mainly due to an isoform matching the C-terminus domain of the full length ErbB3 185kDa receptor. Nuclear staining was also restricted to cancer cells and was increased in advanced castration-resistant prostate cancer when compared to localized tumours, suggesting it could be involved in the progression of prostate cancer up to the terminal castration-resistant stage. ChIP-on-chip experiments were performed on immortalized and tumour cell lines selected upon characterization of endogenous nuclear expression of an ErbB3 80kDa isoform. Among the 1840 target promoters identified, 26 were selected before ErbB3 80kDa -dependent gene expression was evaluated by real-time quantitative RT-PCR, providing evidence that ErbB3 80kDa exerted transcriptional control on those genes. Some targets are already known to be involved in prostate cancer progression even though no link was previously established with ErbB3 membrane and/or nuclear signalling. Many others, not yet associated with prostate cancer, could provide new therapeutic possibilities for patients expressing ErbB3 80kDa . Detecting ErbB3 80kDa could thus constitute a useful marker of prognosis and response to therapy.