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Carcinogenesis Advance Access originally published online on June 14, 2006
Carcinogenesis 2007 28(1):49-59; doi:10.1093/carcin/bgl091
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells

Margit Pacher, Michael J. Seewald, Mario Mikula1, Susanne Oehler, Maurice Mogg, Ursula Vinatzer, Andreas Eger2, Norbert Schweifer3, Roland Varecka3, Wolfgang Sommergruber3, Wolfgang Mikulits1 and Martin Schreiber*

Department of Obstetrics and Gynecology, Medical University of Vienna A-1090 Vienna, Austria
1 Department of Internal Medicine I, Medical University of Vienna A-1090 Vienna, Austria
2 Department of Medical Biochemistry, Medical University of Vienna A-1090 Vienna, Austria
3 Boehringer Ingelheim Austria A-1120 Vienna, Austria

*To whom correspondence should be addressed Email: martin.schreiber{at}meduniwien.ac.at

Insulin-like growth factor (IGF) signaling is a key regulator of breast development and breast cancer. We have analyzed the expression of the IGF signaling cascade in 17 human breast cancer and 4 mammary epithelial cell lines. Five cell lines expressed high levels of IGF1 receptor, insulin (INS)/IGF receptor substrate 1, IGF-binding proteins 2 and 4, as well as the estrogen receptor (ESR), indicating a co-activation of IGF and ESR signaling. Next, we stably overexpressed IGF1 and IGF2 in MCF7 breast cancer cells, which did not affect their epithelial characteristics and the expression and localization of the epithelial marker genes E-cadherin and ß-catenin. Conversely, IGF1 and IGF2 overexpression potently increased cellular proliferation rates and the efficiency of tumor formation in mouse xenograft experiments, whereas the resistance to chemotherapeutic drugs such as taxol was unaltered. Expression profiling of overexpressing cells with whole-genome oligonucleotide microarrays revealed that 21 genes were upregulated >2-fold by both IGF1 and IGF2, 9 by IGF1, and 9 by IGF2. Half of the genes found to be upregulated are involved in transport and biosynthesis of amino acids, including several amino acid transport proteins, argininosuccinate and asparagine synthetases, and methionyl-tRNA synthetase. Upregulation of these genes constitutes a novel mechanism apparently contributing to the stimulatory effects of IGF signaling on the global protein synthesis rate. We conclude that the induction of cell proliferation and tumor formation by long-term IGF stimulation may primarily be due to anabolic effects, in particular increased amino acid production and uptake.


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