TY - JOUR
T1 - Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development
AU - Grimm, Sandra L.
AU - Seagroves, Tiffany N.
AU - Kabotyanski, Elena B.
AU - Hovey, Russell C.
AU - Vonderhaar, Barbara K.
AU - Lydon, John P.
AU - Miyoshi, Keiko
AU - Hennighausen, Lothar
AU - Ormandy, Christopher J.
AU - Lee, Adrian V.
AU - Stull, Malinda A.
AU - Wood, Teresa L.
AU - Rosen, Jeffrey M.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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/EBPβnull mice. PR patterning was also altered in PrIRnull mice, as well as in mammary tissue transplants from both PrIRnull 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/EBPβnull 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/EBPβnull 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/EBPβnull 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.
AB - 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/EBPβnull mice. PR patterning was also altered in PrIRnull mice, as well as in mammary tissue transplants from both PrIRnull 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/EBPβnull 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/EBPβnull 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/EBPβnull 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.
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U2 - 10.1210/me.2002-0239
DO - 10.1210/me.2002-0239
M3 - Article
C2 - 12456789
AN - SCOPUS:12244294465
VL - 16
SP - 2675
EP - 2691
JO - Molecular Endocrinology
JF - Molecular Endocrinology
SN - 0888-8809
IS - 12
ER -