title: Putting the brakes on mammary tumorigenesis: loss of STAT1 predisposes to intraepithelial neoplasias.
abstract: 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.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Schneckenleithner
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.forename: Nina
authors.initials: N
authors.lastname: Neugebauer
authors.forename: Karoline
authors.initials: K
authors.lastname: Kollmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Kolbe
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D061354:Acinar Cells / Q000166:cytology; D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
chemical_list: D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse