TY - JOUR
T1 - Putting the brakes on mammary tumorigenesis
T2 - Loss of STAT1 predisposes to intraepithelial neoplasias
AU - Schneckenleithner, Christine
AU - Bago-Horvath, Zsuzsanna
AU - Dolznig, Helmut
AU - Neugebauer, Nina
AU - Kollmann, Karoline
AU - Kolbe, Thomas
AU - Decker, Thomas
AU - Kerjaschki, Dontscho
AU - Wagner, Kay Uwe
AU - Müller, Mathias
AU - Stoiber, Dagmar
AU - Sexl, Veronika
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - IRF1
KW - MIN
KW - Mammary cancer
KW - Stat1
KW - Tumorsurveillance
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U2 - 10.18632/oncotarget.371
DO - 10.18632/oncotarget.371
M3 - Article
C2 - 22185785
AN - SCOPUS:84862980088
VL - 2
SP - 1043
EP - 1054
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 12
ER -