title: Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Margit
authors.initials: M
authors.lastname: Pacher
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seewald
authors.forename: Mario
authors.initials: M
authors.lastname: Mikula
authors.forename: Susanne
authors.initials: S
authors.lastname: Oehler
authors.forename: Maurice
authors.initials: M
authors.lastname: Mogg
authors.forename: Ursula
authors.initials: U
authors.lastname: Vinatzer
authors.forename: Andreas
authors.initials: A
authors.lastname: Eger
authors.forename: Norbert
authors.initials: N
authors.lastname: Schweifer
authors.forename: Roland
authors.initials: R
authors.lastname: Varecka
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sommergruber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.forename: Martin
authors.initials: M
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005455:Fluorescent Antibody Technique; D015894:Genome, Human; D006801:Humans; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017239:Paclitaxel; D013936:Thymidine