Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis

Abstract

The neu (c-erbB-2, Her-2) protooncogene is amplified and overexpressed in 20-30% of human breast cancers. Although transgenic mouse models have illustrated the role of Neu in the induction of mammary tumors, Neu expression in these models is driven by a strong viral promoter of questionable relevance to the human disease. To ascertain whether expression of activated Neu under the control of the endogenous promoter in the mammary gland could induce mammary tumors we have generated mice that conditionally express activated Neu under the transcriptional control of the intact endogenous Neu promoter. Expression of oncogenic neu in the mammary gland resulted in accelerated lobulo-alveolar development and formation of focal mammary tumors after a long latency period. However, expression of activated Neu under the normal transcriptional control of the endogenous promoter was not sufficient for the initiation of mammary carcinogenesis. Strikingly, all mammary tumors bear amplified copies (2-22 copies) of the activated neu allele relative to the wild-type allele and express highly elevated levels of neu transcript and protein. Thus, like human erbB-2-positive breast tumors, mammary tumorigenesis in this mouse model requires the amplification and commensurate elevated expression of the neu gene.

Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor

“…To limit the possibility of deleterious consequences, the part of ICD with the most transforming activity of HER -2/ neu molecule was deleted. 31 We then infected DCs with this adenoviral vector and investigated the anti -HER2/neu immune responses by DC HER -2 vaccination in an animal model using a murine tumor cell line MCA26 /HER -2 engineered to express HER -2 /neu antigen. We chose to use Ad vectors for gene transfer into DCs because these viruses can infect DCs with high efficiency and easily allow introduction of multiple adenoviral vectors into a single cell.…”

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

“…Transgenic mice MMTV-Neu-IRES-CRE (NIC), MMTV-CRE and ILK flox mice were generated and characterized previously (Andrechek et al, 2000;Terpstra et al, 2003;Troussard et al, 2003;Ursini-Siegel et al, 2008) GTRosa26 mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). The CAG-CAT-EGFP reporter mice were described previously (Kawamoto et al, 2000;Ahmed et al, 2002).…”

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

“…To more closely mimic events involved in ErbB2-induced mammary tumor progression, we derived transgenic mice that carry a Cre-inducible activated erbB2 under the transcriptional control of the endogenous erbB2 promoter (herein referred to as the ErbB2 knock-in mouse model [ErbB2 KI ] strain) (14). In contrast to the rapid tumor progression observed in the mouse mammary tumor virus (MMTV)-activated erbB2 strains, focal mammary tumors arose only after an extended latency period in these strains.…”