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-beta (C/EBPbeta), 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 (PrlR) expression were observed while screening for differentially expressed genes in C/EBPbeta(null) mice. PR patterning was also altered in PrlR(null) mice, as well as in mammary tissue transplants from both PrlR(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/EBPbeta(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/EBPbeta(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/EBPbeta(null) mice. Together, these data suggest that C/EBPbeta is a master regulator of mammary epithelial cell fate and that the correct spatial pattern of PR and PrlR expression is a critical determinant of hormone-regulated cell proliferation.