Characterization of a novel primary mammary tumor cell line reveals that cyclin D1 is regulated by the type I insulin-like growth factor receptor.

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.

• Authors: Robert A Jones, Craig I Campbell, James J Petrik, Roger A Moorehead
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 6 Issue 5 Pg. 819-28 (May 2008) ISSN: 1541-7786 [Print] United States
• PMID: 18505926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• RNA, Messenger
• Cyclin D1
• Receptor, IGF Type 1

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cyclin D1 (biosynthesis)
• Gene Expression Regulation, Neoplastic
• Ligands
• Mammary Neoplasms, Animal (metabolism)
• Mice
• Mice, Transgenic
• Oligonucleotide Array Sequence Analysis
• Phosphorylation
• RNA, Messenger (metabolism)
• Receptor, IGF Type 1 (metabolism)
• Time Factors