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

Mammary gland involution is characterized by extensive apoptosis of the epi thelial cells. At the onset of involution, Stat3 is specifically activated. To address the function of this signaling molecule in mammary epithelial a poptosis, we have generated a conditional knockout of Stat3 using the Cre-l ox recombination system. Following weaning, a decrease in apoptosis and a d ramatic delay of involution occurred in Stat3 null mammary tissue. Involuti on is normally associated with a significant increase in IGFBP-5 levels. Th is 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 mic elles, thereby inhibiting its survival function. Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is es sential to normal involution. No marked differences were seen in the regula tion of Stat5, Bcl-x(L), or Bax in the absence of Stat3. Precocious activat ion 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 impor tance of a Stat factor in signaling the initiation of physiological apoptos is in vivo.