Integrated and Functional Genomics Analysis Validates the Relevance of the Nuclear Variant ErbB380kDa in Prostate Cancer Progression.

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 ErbB3185kDa 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 ErbB380kDa isoform. Among the 1840 target promoters identified, 26 were selected before ErbB380kDa-dependent gene expression was evaluated by real-time quantitative RT-PCR, providing evidence that ErbB380kDa 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 ErbB380kDa. Detecting ErbB380kDa could thus constitute a useful marker of prognosis and response to therapy.

PloS one. 2016 May 18*** epublish ***

Mahmoud El Maassarani, Alice Barbarin, Gaëlle Fromont, Ouafae Kaissi, Margot Lebbe, Brigitte Vannier, Ahmed Moussa, Paule Séité

Equipe 2RCT, Université de Poitiers, Faculté des Sciences Fondamentales, Pôle Biologie- Santé, 1 rue G. Bonnet, 86073, Poitiers cedex 9, France., Equipe 2RCT, Université de Poitiers, Faculté des Sciences Fondamentales, Pôle Biologie- Santé, 1 rue G. Bonnet, 86073, Poitiers cedex 9, France., Centre Hospitalier Universitaire Bretonneau, Laboratoire d'Anatomopathologie, INSERM U1069, 37000 Tours, France., LTI Laboratory, Abdelmalek Essaadi University, ENSAT, BP 1818, 90 000 Tangier, Morocco., Equipe 2RCT, Université de Poitiers, Faculté des Sciences Fondamentales, Pôle Biologie- Santé, 1 rue G. Bonnet, 86073, Poitiers cedex 9, France., Equipe 2RCT, Université de Poitiers, Faculté des Sciences Fondamentales, Pôle Biologie- Santé, 1 rue G. Bonnet, 86073, Poitiers cedex 9, France., LTI Laboratory, Abdelmalek Essaadi University, ENSAT, BP 1818, 90 000 Tangier, Morocco., Equipe 2RCT, Université de Poitiers, Faculté des Sciences Fondamentales, Pôle Biologie- Santé, 1 rue G. Bonnet, 86073, Poitiers cedex 9, France.