The Human Splice Variant Δ16HER2 Induces Rapid Tumor Onset in a Reporter Transgenic Mouse

University of California, Los Angeles, and Cedars-Sinai Medical Center, United States of America
PLoS ONE (Impact Factor: 3.53). 04/2011; 6(4):e18727. DOI: 10.1371/journal.pone.0018727
Source: PubMed

ABSTRACT Several transgenic mice models solidly support the hypothesis that HER2 (ERBB2) overexpression or mutation promotes tumorigenesis. Recently, a HER2 splice variant lacking exon-16 (Δ16HER2) has been detected in human breast carcinomas. This alternative protein, a normal byproduct of HER2, has an increased transforming potency compared to wild-type (wt) HER2 receptors. To examine the ability of Δ16HER2 to transform mammary epithelium in vivo and to monitor Δ16HER2-driven tumorigenesis in live mice, we generated and characterized a mouse line that transgenically expresses both human Δ16HER2 and firefly luciferase under the transcriptional control of the MMTV promoter. All the transgenic females developed multifocal mammary tumors with a rapid onset and an average latency of 15.11 weeks. Immunohistochemical analysis revealed the concurrent expression of luciferase and the human Δ16HER2 oncogene only in the mammary gland and in strict correlation with tumor development. Transgenic Δ16HER2 expressed on the tumor cell plasma membrane from spontaneous mammary adenocarcinomas formed constitutively active homodimers able to activate the oncogenic signal transduction pathway mediated through Src kinase. These new transgenic animals demonstrate the ability of the human Δ16HER2 isoform to transform "per se" mammary epithelium in vivo. The high tumor incidence as well as the short latency strongly suggests that the Δ16HER2 splice variant represents the transforming form of the HER2 oncoprotein.

Download full-text


Available from: Augusto Amici, Aug 06, 2015
  • Source
    • "In addition to dasatinib, other tyrosine kinase inhibitors such as erlotinib, emodin, lapatinib and gefitinib are effective in treating trastuzumab-resistant breast tumors. (Marchini et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: HER2 overexpression has been observed in 20-30% of breast cancer cases. In addition to main products of HER2 gene, there are other variations, of which, the most important one is Δ16HER2. In principle, although HER2 overexpression is the first step for carcinogenesis, it is not sufficient, and the main reason responsible for breast tumorigenesis is Δ16HER2. This onco-protein, which lacks exon 16, can form stable homodimers remaining active constitutively. Like Δ16HER2, 611-CTF, a specific HER2 carboxy-terminal fragment, expresses a constitutively active homodimers. Therefore, targeting of Δ16HER2 and 611-CTF is the most promising strategy for treating HER2+ breast cancer. Along with inhibitors of HER2 gene products, miRNAs are also novel candidates for treatment of breast malignancy. Several drugs, working against different domains of the HER2 receptor, have been presented for treatment of HER2 positive breast cancers and they can increase mortality in patients.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is a heterogeneous disease and consequently an exact diagnosis is as important as the actual therapy. Therefore, identification of novel diagnostic biomarker targets is urgently needed. Physiological and pathological changes are reflected by post-translational modifications of proteins. Each post-translational modification (e.g., proteolytic cleavage) is the result of a specific local process and may produce disease-specific neoepitopes. Neoepitopes have been successfully used as biomarkers in many diseases, and may also serve as promising tools in the development of future diagnostic assays within oncology. By specifically targeting neoepitopes, more information regarding disease-type and -state may be obtained and future research into neoepitopes will provide important and novel means for the diagnosis, prognosis and treatment efficacy in cancer. In this paper, we focus on protein ectodomain shedding and the generation of neoepitopes as future noninvasive (serological) cancer biomarkers. We use the protein ectodomain shedding of the human epidermal growth factor receptor 2, which is associated with breast cancer, as an example. We assess the current status of measuring human epidermal growth factor receptor 2 and discuss how this potentially could be improved. Furthermore, we expand the discussion to include examples of other cancer associated proteins.
    Future Oncology 01/2013; 9(1):35-44. DOI:10.2217/fon.12.161 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bioluminescent imaging (BLI) is a powerful noninvasive tool that has dramatically accelerated the in vivo interrogation of cancer systems and longitudinal analysis of mouse models of cancer over the past decade. Various luciferase enzymes have been genetically engineered into mouse models (GEMM) of cancer, which permit investigation of cellular and molecular events associated with oncogenic transcription, posttranslational processing, protein-protein interactions, transformation, and oncogene addiction in live cells and animals. Luciferase-coupled GEMMs ultimately serve as a noninvasive, repetitive, longitudinal, and physiologic means by which cancer systems and therapeutic responses can be investigated accurately within the autochthonous context of a living animal.
    Cancer Discovery 04/2013; 3(6). DOI:10.1158/2159-8290.CD-12-0503 · 19.45 Impact Factor
Show more