Abstract
The importance of type I insulin-like growth factor receptor (IGF-IR) overexpression in mammary tumorigenesis was recently shown in two separate transgenic models. One of these models, the MTB-IGFIR transgenics, was generated in our lab to overexpress IGF-IR in mammary epithelial cells in a doxycycline (Dox)-inducible manner. To complement this transgenic model, primary cells that retained Dox-inducible expression of IGF-IR were isolated from a transgenic mammary tumor. This cell line, RM11A, expressed high levels of IGF-IR, phosphorylated Akt, and phosphorylated extracellular signal-regulated kinase 1/2 in the presence of Dox. IGF-IR overexpression provided the primary tumor cells with a survival advantage in serum-free media and seemed to induce ligand-independent activation of the IGF-IR because RM11A cells cultured in the presence of Dox were largely nonresponsive to exogenous IGFs. IGF-IR overexpression also augmented the growth of RM11A cells in vivo because injection of these cells into mammary glands of wild-type mice produced palpable tumors in 15.8 +/- 3.4 days when the mice were administered Dox, compared with 57.8 +/- 6.3 days in the absence of Dox. DNA microarray analysis revealed a number of genes regulated by IGF-IR, one of which was cyclin D1. Suppression of IGF-IR expression in vitro or in vivo was associated with a decrease in cyclin D1 protein, suggesting that at least some of the proliferative actions of IGF-IR are mediated through cyclin D1. Therefore, this article characterizes the first primary murine mammary tumor cell line with inducible IGF-IR expression. These cells provide a powerful in vitro/in vivo model to examine the function of IGF-IR in mammary tumorigenesis.
Highlights
The type I insulin-like growth factor receptor (IGF-IR)plays an important role in a number of human cancers including those of the lung, breast, and prostate [1,2,3,4,5]
We have previously shown that transgenic overexpression of IGF-IR in the mammary epithelium in a Dox-dependent manner results in the rapid development of mammary tumors [37]
To further investigate the role of IGF-IR in mammary tumorigenesis, we isolated several cell lines from an MTB-IGFIR mammary tumor. One of these cell lines, termed RM11A, was identified as containing IGF-IR levels that could be induced by Dox (Fig. 1A)
Summary
The type I insulin-like growth factor receptor (IGF-IR)plays an important role in a number of human cancers including those of the lung, breast, and prostate [1,2,3,4,5]. The type I insulin-like growth factor receptor (IGF-IR). The physiologic effects of IGF-IR are mediated through a number of signaling pathways including phosphatidylinositol 3-kinase and mitogenactivated protein kinase. Activation of the tyrosine kinase domain following binding of IGF-I or IGF-II permits the association of a number of intracellular docking proteins including Shc and insulin receptor substrate 1. Induction of the Shc pathway leads to extracellular signal – regulated kinase (Erk)-1/ Erk phosphorylation and activation of downstream transcription factors that regulate cell cycle progression [1, 3, 4, 6,7,8]. Phosphorylation of insulin receptor substrate 1 leads to sequential activation of phosphatidylinositol 3-kinase and Akt [9,10,11]. Other signaling pathways activated by IGF-IR include p38 mitogen-activated protein kinase and c-jun NH2-terminal kinase/stress-activated protein kinase [18]
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