Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells
| Autor: | Norbert Schweifer, Michael J. Seewald, Andreas Eger, Wolfgang Sommergruber, Martin Schreiber, Mario Mikula, Ursula Vinatzer, Margit Pacher, Susanne Oehler, Roland Varecka, Maurice Mogg, Wolfgang Mikulits |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
medicine.medical_specialty Paclitaxel Transcription Genetic Cell Survival medicine.medical_treatment Blotting Western Transplantation Heterologous Fluorescent Antibody Technique Mice Nude Estrogen receptor Breast Neoplasms Mice SCID Immunoenzyme Techniques Mice Downregulation and upregulation Insulin-Like Growth Factor II Internal medicine Tumor Cells Cultured medicine Animals Humans Insulin-Like Growth Factor I Receptor Cell Proliferation Oligonucleotide Array Sequence Analysis Mice Inbred BALB C biology Genome Human Reverse Transcriptase Polymerase Chain Reaction Cell growth Growth factor General Medicine Cell biology Endocrinology Drug Resistance Neoplasm Insulin-like growth factor 2 Cancer cell biology.protein Female Signal transduction Signal Transduction Thymidine |
| Zdroj: | Carcinogenesis. 28:49-59 |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | 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 beta-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. |
| Databáze: | OpenAIRE |
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