Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias
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1 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
2 Clinical Institute of Pathology, Medical University of Vienna, Austria
3 Institute of Medical Genetics, Medical University of Vienna, Austria
4 Biomodels Austria, University of Veterinary Medicine, Vienna and Biotechnology in Animal Production, IFA-Tulln, University of Natural Resources and Applied Life Sciences, Vienna
5 Max F. Perutz Laboratories, Department of Genetics, Microbiology and Immunobiology, University of Vienna, Austria
6 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
7 Institute of Animal Breeding and Genetics and Biomodels Austria, University of Veterinary Medicine, Vienna, Austria
8 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
9 Institute of Pharmacology, Medical University of Vienna, Austria
Received: December 1, 2011; Accepted: December 2, 2011; Published: December 19, 2011;
Keywords: Stat1, MIN, IRF1, mammary cancer, tumorsurveillance
Veronika Sexl, email:
Multiparous Stat1-/- mice spontaneously develop mammary tumors with increased incidence: at an average age of 12 months, 55% of the animals suffer from mammary cancer, although the histopathology is heterogeneous. We consistently observed mosaic expression or down-regulation of STAT1 protein in wild-type mammary cancer evolving in the control group. Transplantation experiments show that tumorigenesis in Stat1-/- mice is partially influenced by impaired CTL mediated tumor surveillance. Additionally, STAT1 exerts an intrinsic tumor suppressing role by controlling and blocking proliferation of the mammary epithelium. Loss of STAT1 in epithelial cells enhances cell growth in both transformed and primary cells. The increased proliferative capacity leads to the loss of structured acini formation in 3D-cultures. Analogous effects were observed when Irf1-/- epithelial cells were used. Accordingly, the rate of mammary intraepithelial neoplasias (MINs) is increased in Stat1-/- animals: MINs represent the first step towards mammary tumors. The experiments characterize STAT1/IRF1 as a key growth inhibitory and tumor suppressive signaling pathway that prevents mammary cancer formation by maintaining growth control. Furthermore, they define the loss of STAT1 as a predisposing event via enhanced MIN formation.
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