c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3
Abstract
Suppressor of cytokine signalling (SOCS) proteins are critical attenuators of cytokine-mediated signalling in diverse tissues. To determine the importance of Socs3 in mammary development, we generated mice in which Socs3 was deleted in mammary epithelial cells. No overt phenotype was evident during pregnancy and lactation, indicating that Socs3 is not a key physiological regulator of prolactin signalling. However, Socs3-deficient mammary glands exhibited a profound increase in epithelial apoptosis and tissue remodelling, resulting in precocious involution. This phenotype was accompanied by augmented Stat3 activation and a marked increase in the level of c-myc. Moreover, induction of c-myc before weaning using an inducible transgenic model recapitulated the Socs3 phenotype, and elevated expression of likely c-myc target genes, E2F-1, Bax and p53, was observed. Our data establish Socs3 as a critical attenuator of pro-apoptotic pathways that act in the developing mammary gland and provide evidence that c-myc regulates apoptosis during involution.
Acknowledgments
We are grateful to D Smith for invaluable advice, D Krebs for expert help with AKT Western blots, B Duscio for excellent assistance, M Le Fleur for advice on zymography, M-L Asselin-Labat and H Barker for discussions and S Mihajlovic for histology. We also wish to thank M Ernst for critical review of the manuscript, as well as B Croker, C Ormandy, D Huang, D Smith, K-U Wagner, D Galloway and P Humbert for generous gifts of mice, antibodies and plasmids. This work was supported by the Victorian Breast Cancer Research Consortium Inc., The Cancer Council Victoria and the National Health and Medical Research Council (Australia).