Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development

Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-β (C/EBPβ), was shown previously to result in aberrant ductal morphogenesis and decreased lobuloalveolar development, accompanied by an altered pattern of progesterone receptor (PR) expression. Here, similar changes in the level and pattern of prolactin receptor (PrIR) expression were observed while screening for differentially expressed genes in C/EBPβ^null mice. PR patterning was also altered in PrIR^null mice, as well as in mammary tissue transplants from both PrIR^null and signal transducer and activator of transcription (Stat) 5a/b-deficient mice, with concomitant defects in hormone-induced proliferation. Down-regulation of PR and activation of Stat5 phosphorylation were seen after estrogen and progesterone treatment in both C/EBPβ^null and wild-type mice, indicating that these signaling pathways were functional, despite the failure of steroid hormones to induce proliferation. IGF binding protein-5, IGF-II, and insulin receptor substrate-1 all displayed altered patterns and levels of expression in C/EBPβ^null mice, suggestive of a change in the IGF signaling axis. In addition, small proline-rich protein (SPRR2A), a marker of epidermal differentiation, and keratin 6 were misexpressed in the mammary epithelium of C/EBPβ^null mice. Together, these data suggest that C/EBPβ is a master regulator of mammary epithelial cell fate and that the correct spatial pattern of PR and PrIR expression is a critical determinant of hormone-regulated cell proliferation.