Carcinogenesis Advance Access published online on June 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgl091
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1 Department of Obstetrics and Gynecology, Medical University of Vienna, A-1090 Vienna, Austria
* To whom correspondence should be addressed. 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. 5 cell lines expressed high levels of IGF1 receptor, insulin/IGF receptor substrate 1, IGF binding proteins 2 and 4, as well as the estrogen receptor, indicating a co-activation of IGF- and estrogen receptor 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 up-regulated more than two-fold by both IGF1 and IGF2, 9 by IGF1, and 9 by IGF2. Half of the genes found to be up-regulated are involved in transport and biosynthesis of amino acids, including several amino acid transport proteins, argininosuccinat- and asparagine synthetases, and methionyl-tRNA synthetase. Up-regulation 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 be primarily due to anabolic effects, in particular increased amino acid production and uptake.
Received September 15, 2005
Revised May 19, 2006
Accepted May 20, 2006
CANCER BIOLOGY
Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells
Margit Pacher 1,
Michael J. Seewald 2,
Mario Mikula 3,
Susanne Oehler 1,
Maurice Mogg 1,
Ursula Vinatzer 1,
Andreas Eger 4,
Norbert Schweifer 2,
Roland Varecka 2,
Wolfgang Sommergruber 2,
Wolfgang Mikulits 3,
and
Martin Schreiber 1 *
2 Boehringer Ingelheim Austria, A-1120 Vienna, Austria
3 Department of Internal Medicine I, Medical University of Vienna, A-1090 Vienna, Austria
4 Department of Medical Biochemistry, Medical University of Vienna, A-1090 Vienna, Austria
Martin Schreiber, E-mail: martin.schreiber{at}meduniwien.ac.at
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