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Disruption of Steroid and Prolactin Receptor Patterning in the Mammary Gland Correlates with a Block in Lobuloalveolar Development

Department of Molecular and Cellular Biology (S.L.G., T.N.S., E.B.K., J.P.L., J.M.R.) and Breast Center (A.V.L.), Department of Medicine, Baylor College of Medicine, Houston, Texas 77030; Molecular and Cellular Endocrinology Section (R.C.H., B.K.V.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, and Laboratory of Genetics and Physiology (K.M., L.H.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Cancer Research Program (C.J.O.), Garvan Institute of Medical Research, Darlinghurst, Australia; and Department of Neuroscience and Anatomy (M.A.S., T.L.W.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Jeffrey M. Rosen, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. E-mail: jrosen{at}bcm.tmc.edu.

Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-ß (C/EBPß), 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/EBPß^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/EBPß^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/EBPß^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/EBPß^null mice. Together, these data suggest that C/EBPß 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR

Ligands:   17β-Estradiol  |  Progesterone

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