Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias

Christine Schneckenleithner, Zsuzsanna Bago-Horvath, Helmut Dolznig, Nina Neugebauer, Karoline Kollmann, Thomas Kolbe, Thomas Decker, Dontscho Kerjaschki, Kay Uwe Wagner, Mathias Müller, Dagmar Stoiber, Veronika Sexl

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1043-1054
Number of pages12
JournalOncotarget
Volume2
Issue number12
DOIs
StatePublished - Dec 2011

Keywords

  • IRF1
  • MIN
  • Mammary cancer
  • Stat1
  • Tumorsurveillance

ASJC Scopus subject areas

  • Oncology

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    Schneckenleithner, C., Bago-Horvath, Z., Dolznig, H., Neugebauer, N., Kollmann, K., Kolbe, T., Decker, T., Kerjaschki, D., Wagner, K. U., Müller, M., Stoiber, D., & Sexl, V. (2011). Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias. Oncotarget, 2(12), 1043-1054. https://doi.org/10.18632/oncotarget.371