Tumor Development by Transgenic Expression of a Constitutively Active Insulin-Like Growth Factor I Receptor

Abstract

The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

“…Mammary gland development in 55-day-old MTB-IGFIR mice was severely disrupted exhibiting a delay in ductal elongation and an apparent increase in ductal side branching compared to control mice. This phenotype is similar to that observed in mice expressing a constitutively active IGF-IR in the mammary epithelium (Carboni et al, 2005). However, ductal branching was difficult to quantify in our transgenics due to the extensive epithelial hyperplasia.…”

“…It is also interesting to note that overexpression of WT IGF-IR starting at 21 days of age our IGF-IR transgenic mice induced mammary tumors with approximately the same latency as the transgenic mice overexpressing an activated version of IGF-IR, presumably since embryonic development (Carboni et al, 2005). Thus, overexpression of the WT IGF-IR is sufficient for mammary epithelial transformation and possesses a similar capacity to transform mammary epithelium as a constitutively active IGF-IR.…”

“…High IGF-IR levels in primary breast tumors have been associated with shorter disease-free survival but not all studies agree on the prognostic value of IGF-IR (Turner et al, 1997;Resnik et al, 1998;Surmacz et al, 1998;Surmacz, 2000). A recent study has shown that overexpression of a constitutively active IGF-IR driven by the mouse mammary tumor virus (MMTV) promoter results in the formation of mammary adenocarcinomas (Carboni et al, 2005). While this study illustrates the oncogenic potential of IGF-IR overexpression in the mammary epithelium, the use of a constitutively active receptor circumvents the complex ligand-receptor dynamics of the native receptor that occurs in vivo.…”

“…Loss of IGF-I or IGF-IR expression in the mammary gland has been shown to result in a decrease in the number of TEBs, ductal branch points and ductal elongation (Ruan and Kleinberg, 1999;Bonnette and Hadsell, 2001;Richards et al, 2004). Delayed ductal growth and a reduction in TEB number was also observed in a transgenic mouse model overexpressing a constitutively activated IGF-IR in the mammary epithjleium (Carboni et al, 2005).…”

“…To date, only one other transgenic mouse overexpressing the type I IGF receptor has been described (Carboni et al, 2005). In this mouse a fusion protein representing the extracellular sequence of CD8a´gene and residues 964-1367 of the human IGF-IR gene was overexpressed using the MMTV promoter (Carboni et al, 2005).…”