The ERBB3 receptor in cancer and cancer gene therapy

Abstract

ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

“…41 It also suppresses ErbB3 when EBP1 binds to it. 42 ErbB3 is an epidermal growth factor receptor (EGFR), and is activated by various growth signals and other EGFR family proteins such as ErbB2. The interactions between EBP1 and ErbB3 are disrupted by the ErbB ligand, heregulin, causing nuclear translocation of EBP1.…”

“…44 Interestingly, RSK and MSK are downstream molecules of ErbB2 and ErbB3 signaling pathway, and heregulin causes increased or prolonged signaling through AKT, ERK, RSK, and MSK cascades. 39 , 42 RSK and MSK were phosphorylated by tRNA Leu overexpression, without growth stimuli such as serum or amino acids. We therefore hypothesized that free tRNA Leu could induce the disruption of the interaction between EBP1 and ErbB3, leading to the inactivation of ErbB3 and/or ErbB2.…”

“…38 , 42 , 47 We therefore investigated the tRNA Leu expression levels in normal and cancer cell lines, based on the tissue origin. According to the results, almost all tRNA Leu isoacceptors tested were more highly expressed in cancer cell lines than in normal cells, irrespective of the tissue type (Fig.…”

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

“…In addition, because the HER3 and HER4 receptors are frequently over-represented in some cancers, [52][53][54] an Ad with HRG-mediated expanded tropism may have potential therapeutic value.…”

“…Moreover, an HRG-targeted virus may be valuable for the treatment of a number of human malignancies, including breast and ovarian carcinomas, in which members of HER receptor family are frequently overexpressed. [50][51][52][53][54] In this regard, Han and co-workers 55 have demonstrated that a recombinant Moloney murine leukemia virus carrying a gp70-HRG fusion envelope protein was able to infect normally refractory human breast cancer cell lines in a receptor-dependent manner.…”