Activating transcription factor 4 overexpression inhibits proliferation and differentiation of mammary epithelium resulting in impaired lactation and accelerated involution.

The basic leucine zipper containing activating transcription factors (ATFs) modulates the expression of growth-regulating genes. In this study, we sought to determine specifically the consequences of ATF4 expression on mammary gland development in transgenic mice. Overexpression of ATF4 severely impaired normal development of the mammary gland, which was associated with reduced proliferation and differentiation of mammary alveolar epithelium and up-regulation of p21(WAF1) and p27(Kip1). In addition, there was also impaired lactation accompanied by decreased expression of alpha-lactoalbumin, whey acidic protein, and beta-casein, possibly because of the down-regulation of STAT5a tyrosine phosphorylation. Mammary gland involution in ATF4-transgenic mice was accelerated, compared with wild type littermates by whole mount analysis. In addition, day 18 of lactation in transgenic mice was phenotypically equivalent to day 3 of involution in wild type mice, as determined by the TUNEL assay and expression of Bax. The concentration of the proapoptotic molecule caspase-3 was increased during lactation in ATF4-transgenic animal. Mammary glands from ATF4-transgenic mice also showed significant nuclear translocation of activated STAT3 and up-regulation of one of its target genes, insulin-like growth factor-binding protein-5, which is thought to facilitate apoptosis by sequestering insulin-like growth factor. Together, these findings suggest that ATF4 may play a role during mammary gland development and that down-regulation of ATF4 may be important for the onset of involution in the mammary gland.