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Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation
- Source :
- Cell cycle (Georgetown, Tex.). 10(5)
- Publication Year :
- 2011
-
Abstract
- The anti-tumor function of Stat1 as a regulator of innate immunity and tumor immune surveillance has been long studied and is well understood; however, less clear is its tumor-site specific role. Although Stat1 phosphorylated at tyrosine (Y) 701 and serine (S) 727 is essential for interferon (IFN) signalling, its function in signalling induced in breast cancer cells is not understood. Herein, we show that Stat1 Y701 phosphorylation is increased in human breast tumor cells with elevated levels of ErbB2/HER-2 and in cells transfected with ErbB2/Neu. However, pharmacological inhibition of ErbB2/HER-2 results in the inhibition of Stat1 Y701 phosphorylation indicating an atypical role of phosphorylated Stat1 in the inhibition of ErbB2/HER-2 signalling. Consistent with this notion, we found that Stat1 suppresses tumor development by an activated form of ErbB2/Neu in mouse embryonic fibroblasts in xenograft tumor assays; however, this anti-tumor function of Stat1 does not rely on Y701 and S727 phosphorylation. Experiments with transgenic mice demonstrated that Stat1 acts to suppress Neu-mediated breast tumorigenesis through immune regulatory and tumor-site specific mechanisms. Our data reveal a previous uncharacterized anti-tumor activity of Stat1 in ErbB2/Neu-mediated cell transformation and breast oncogenesis with possible implications in the diagnosis and treatment of ErbB2-positive breast cancers.
- Subjects :
- Genetically modified mouse
Receptor, ErbB-2
Transplantation, Heterologous
Antineoplastic Agents
Mice, Transgenic
Biology
Malignant transformation
Cell Line
Mice
Mammary Glands, Animal
Interferon
Chlorocebus aethiops
medicine
Animals
Humans
Protein phosphorylation
Tyrosine
Phosphorylation
skin and connective tissue diseases
Molecular Biology
Innate immune system
Mammary Neoplasms, Experimental
Gefitinib
Lapatinib
Cell Biology
Transfection
Cell Transformation, Neoplastic
STAT1 Transcription Factor
Cancer research
Disease Progression
Quinazolines
Female
Developmental Biology
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 15514005
- Volume :
- 10
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cell cycle (Georgetown, Tex.)
- Accession number :
- edsair.doi.dedup.....807e5f8945dff12eebbba25f33cb2543