Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3

  1. Rachel S. Chapman,
  2. Paula C. Lourenco,
  3. Elizabeth Tonner,
  4. David J. Flint,
  5. Stefan Selbert,
  6. Kiyoshi Takeda,
  7. Shizuo Akira,
  8. Alan R. Clarke, and
  9. Christine J. Watson
  1. Cancer Research Campaign (CRC) Laboratories, Department of Pathology, University of Edinburgh, Medical School, Edinburgh EH8 9AG UK; Hannah Research Institute, Ayr, Scotland KA6 5HL UK; Department of Host Defence, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

Abstract

Mammary gland involution is characterized by extensive apoptosis of the epithelial cells. At the onset of involution, Stat3 is specifically activated. To address the function of this signaling molecule in mammary epithelial apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox recombination system. Following weaning, a decrease in apoptosis and a dramatic delay of involution occurred in Stat3 null mammary tissue. Involution is normally associated with a significant increase in IGFBP-5 levels. This was observed in control glands, but not in the absence of Stat3. IGFBP-5 has been suggested to induce apoptosis by sequestering IGF-1 to casein micelles, thereby inhibiting its survival function. Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution. No marked differences were seen in the regulation of Stat5, Bcl-xL, or Bax in the absence of Stat3. Precocious activation of Stat1 and increases in levels of p53 and p21 occurred and may act as compensatory mechanisms for the eventual initiation of involution observed in Stat3 null mammary glands. This is the first demonstration of the importance of a Stat factor in signaling the initiation of physiological apoptosis in vivo.

Keywords

Footnotes

  • Corresponding author. Present address: Department of Pathology, University of Cambridge, Cambridge CB2 1QP UK.

  • E-MAIL cjw53{at}mole.bio.cam.ac.uk; FAX 44 1223 333346.

    • Received March 1, 1999.
    • Accepted August 4, 1999.
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