The nucleolus is a nuclear domain that is the primary site of transcription of the ribosomal genes (rDNA) by RNA Polymerase I. Rapid growth and division of cells, including tumor ones, is correlated with intensive protein biosynthesis. Different factors that induce cellular stress also often results in ribosome biogenesis impairment that triggers pathways that direct cells to new destinations such as cell cycle arrest, damage repair, differentiation, autophagy, programmed cell death or aging. They are also triggered as a response to oncogenic factor overexpression to protect tissues and organs against extensive proliferation of abnormal cells. Our preliminary results address towards possible link between ErbB3 receptor, a member of EGFR family known to be involved in cell proliferation, with nucleolar function. ErbB3 localizes in the nucleolus but its function in this subnuclear compartment is unknown. This receptor represent an emerging cancer target because it plays an important role in drug resistance therapies: interfere with the function of ErbB3 nucleolar variant could be a new strategy used in cancer therapy.
EGFR and ERBB2, have been extensively targeted for cancer drug development. EGFR is being targeted with the monoclonal antibody cetuximab and with two tyrosine kinase inhibitors, gefitinib and erlotinib. ERBB2 has been targeted by the monoclonal antibody trastuzumab (Herceptin), where it is often overexpressed. Evident clinical efficacies these therapies have limitations with a significant proportion of tumors still resisting to treatment. Recent evidence has suggested that ERBB3 is responsible for tumor progression and resistance to therapeutic agents: there are compelling results showing that ERbB3 activity up-regulation is a means of escape from therapeutic suppression by tyrosine kinase inhibitors in breast cancer. These evidences have triggered major efforts towards the development of anti-ErbB3 therapies. Because this receptor is devoid of strong intrinsic kinase activity, the major strategy in this case is the generation of monoclonal antibodies directed against the receptor. An suggestive alternative may be targeting the nucleolar variant of intracellular ErbB3 by specific antibody.