C/EBPβ, but not C/EBPα, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland
10.1101/gad.12.12.1917
Crossref journal-article
Cold Spring Harbor Laboratory
Genes & Development (246)
Abstract

The CCAAT/enhancer binding proteins (C/EBPs) are differentially expressed throughout mammary gland development and interact with binding sites within the promoter of a milk protein gene, β-casein. The specific roles of C/EBPβ and C/EBPα in mouse mammary gland development and differentiation have been investigated in mice that carry targeted deletions of these genes. C/EBPβ−/− virgin mice exhibited cystic, enlarged mammary ducts with decreased secondary branching. Transplantation of C/EBPβ−/− mammary epithelium into the cleared mammary fat pads of nude mice confirmed that this defect in ductal morphogenesis was intrinsic to the epithelium. When treated with estrogen/progesterone (E+P) to simulate pregnancy, C/EBPβ−/− mammary glands displayed only limited lobuloalveolar development and ductal side branching. Primary mammary epithelial cells obtained from E+P-treated C/EBPβ−/−mice that were cultured on extracellular matrix gels did not functionally differentiate in response to lactogenic hormones despite their organization into three-dimensional structures. Expression of β-casein protein was inhibited 85%–100% and whey acidic protein (WAP) was undetectable. In contrast, no detectable alterations in mammary development or β-casein expression were observed in mammary outgrowths derived from newborn C/EBPα−/− mammary epithelium transplanted into the cleared mammary fat pads of syngeneic hosts. These results demonstrate that C/EBPβ, but not C/EBPα, is required for ductal morphogenesis, lobuloalveolar development, and functional differentiation of mammary epithelial cells.

Authors 7
  1. Tiffany N. Seagroves (first)
  2. Susanne Krnacik (additional)
  3. Brian Raught (additional)
  4. Jason Gay (additional)
  5. Bonnie Burgess-Beusse (additional)
  6. Gretchen J. Darlington (additional)
  7. Jeffrey M. Rosen (additional)
References 58 Referenced 205
  1. 10.1016/S0021-9258(18)42720-2 / J. Biol. Chem. / Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. by Alam (1992)
  2. {'key': '2021111418543469000_12.12.1917.2', 'first-page': '251', 'article-title': 'Dynamic reciprocity: How do extracellular matrix and hormones direct gene expression?', 'volume': '249', 'author': 'Bissell', 'year': '1987', 'journal-title': 'Prog. Clin. Biol. Res.'} / Prog. Clin. Biol. Res. / Dynamic reciprocity: How do extracellular matrix and hormones direct gene expression? by Bissell (1987)
  3. 10.1002/aja.1002040109 / Dev. Dyn. / CCAAT/enhancer binding protein isoforms expression in the colon of neonatal mice. by Blais (1995)
  4. 10.1002/j.1460-2075.1994.tb06328.x / EMBO J. / LAP (NF-IL-6), a tissue-specific transcriptional activator, is an inhibitor of hepatoma cell proliferation. by Buck (1994)
  5. 10.1101/gad.5.9.1538
  6. 10.1101/gad.10.21.2794
  7. 10.1073/pnas.93.1.465
  8. 10.1073/pnas.81.7.1991
  9. {'key': '2021111418543469000_12.12.1917.9', 'first-page': '515', 'article-title': 'Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice.', 'volume': '78', 'author': 'DeOme', 'year': '1959', 'journal-title': 'Cancer Res.'} / Cancer Res. / Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. by DeOme (1959)
  10. 10.1016/0092-8674(91)90531-3
  11. 10.1016/0016-5085(94)90420-0 / Gastroenterology / Selective induction of CCAAT/enhancer binding protein isoforms occurs during rat liver development. by Diehl (1994)
  12. 10.1101/gad.9.19.2364
  13. 10.1002/(SICI)1097-4652(199802)174:2<232::AID-JCP10>3.0.CO;2-E
  14. 10.1093/nar/23.22.4726
  15. 10.1101/gad.12.4.449
  16. 10.1074/jbc.272.22.14263
  17. 10.1242/dev.122.12.4013 / Development / Apoptosis in the terminal endbud of the murine mammary gland: A mechanism of ductal morphogenesis. by Humphreys (1996)
  18. 10.1242/jcs.110.11.1261 / J. Cell. Sci. / Fibroblast growth factor receptor signalling has a role in lobuloalveolar development of the mammary gland. by Jackson (1997)
  19. 10.3168/jds.S0022-0302(84)81267-9 / J. Dairy Sci. / Immunochemical characterization with monoclonal antibodies of three major caseins and alpha-lactalbumin from rat milk. by Kaetzel (1984)
  20. 10.1093/nar/23.20.4097
  21. 10.1101/gad.2.7.786
  22. 10.1128/MCB.17.4.2038 / Mol. Cell. Biol. / The ability of C/EBP beta but not C/EBP alpha to synergize with an Sp1 protein is specified by the leucine zipper and activation domain. by Lee (1997)
  23. 10.1073/pnas.91.19.8757
  24. 10.1073/pnas.90.20.9606
  25. 10.1101/gad.11.2.179
  26. 10.1101/gad.9.18.2266
  27. 10.1242/dev.121.8.2255 / Development / The breathless FGF receptor homolog, a downstream target of Drosophila C/EBP in the developmental control of cell migration. by Murphy (1995)
  28. 10.1101/gad.11.2.167
  29. 10.1073/pnas.90.17.8219
  30. 10.1210/en.133.5.2327
  31. Pullan S.E. Streuli C.H. (1996) The mammary gland epithelial cell. in Epithelial cell culture, ed Harris A. (Cambridge University Press, Cambridge, UK), pp 97–121.
  32. 10.1128/MCB.14.9.5858
  33. 10.1210/me.9.9.1223
  34. {'key': '2021111418543469000_12.12.1917.34', 'first-page': '4382', 'article-title': 'Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein β isoform and up-regulation of the eukaryotic translation initiation factor 2α are correlated with neoplastic transformation of mammary epithelial cells.', 'volume': '56', 'author': 'Raught', 'year': '1996', 'journal-title': 'Cancer Res.'} / Cancer Res. / Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein β isoform and up-regulation of the eukaryotic translation initiation factor 2α are correlated with neoplastic transformation of mammary epithelial cells. by Raught (1996)
  35. 10.1016/0925-4773(95)00407-R
  36. 10.1101/gad.8.4.428
  37. Robinson, G.W., P.F. Johnson, L. Hennighausen, and E. Sterneck. 1998. The C/EBPβ transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland. Genes & Dev. (this issue).. (10.1101/gad.12.12.1907)
  38. 10.1016/S0021-9258(17)39682-5 / J. Biol. Chem. / Synthetic peptides corresponding to keratin subunits elicit highly specific antibodies. by Roop (1984)
  39. {'key': '2021111418543469000_12.12.1917.39', 'first-page': '101', 'article-title': 'Composite response elements mediate hormonal and developmental regulation of milk protein gene expression.', 'volume': '63', 'author': 'Rosen', 'year': '1997', 'journal-title': 'Biochem. Soc. Symp.'} / Biochem. Soc. Symp. / Composite response elements mediate hormonal and developmental regulation of milk protein gene expression. by Rosen (1997)
  40. 10.1016/0955-0674(95)80117-0
  41. 10.1242/dev.122.5.1395 / Development / Development of the Drosophila tracheal system occurs by a series of morphologically distinct but genetically coupled branching events. by Samakovlis (1996)
  42. 10.1002/j.1460-2075.1995.tb07185.x / EMBO J. / Lymphoproliferative disorder and imbalanced T- helper response in C/EBPβ-deficient mice. by Screpanti (1995)
  43. 10.1007/BF02528777
  44. 10.1016/0092-8674(95)90034-9
  45. 10.1101/gad.11.17.2153
  46. 10.1016/0092-8674(95)90418-2
  47. 10.1093/emboj/16.24.7432
  48. 10.1128/MCB.17.12.7353 / Mol. Cell. Biol. / CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice. by Timchenko (1997)
  49. 10.1038/386713a0
  50. 10.1073/pnas.94.14.7239
  51. 10.1126/science.1987644
  52. 10.1126/science.7652557
  53. 10.1101/gad.5.9.1553
  54. 10.1002/j.1460-2075.1995.tb07319.x / EMBO J. / CRP2 (C/EBP beta) contains a bipartite regulatory domain that controls transcriptional activation, DNA binding and cell specificity. by Williams (1995)
  55. 10.1101/gad.9.2.168
  56. {'key': '2021111418543469000_12.12.1917.56', 'first-page': '1015', 'article-title': 'Keratinocyte growth factor causes cystic dilation of the mammary glands of mice. Interactions of keratinocyte growth factor, estrogen, and progesterone in vivo.', 'volume': '145', 'author': 'Yi', 'year': '1994', 'journal-title': 'Am. J. Pathol.'} / Am. J. Pathol. / Keratinocyte growth factor causes cystic dilation of the mammary glands of mice. Interactions of keratinocyte growth factor, estrogen, and progesterone in vivo. by Yi (1994)
  57. 10.1093/jnci/89.24.1887
  58. 10.1073/pnas.94.2.569
Dates
Type When
Created 17 years, 6 months ago (Feb. 20, 2008, 5:52 p.m.)
Deposited 3 years, 9 months ago (Nov. 14, 2021, 10:18 p.m.)
Indexed 2 months ago (July 1, 2025, 9:49 a.m.)
Issued 27 years, 2 months ago (June 15, 1998)
Published 27 years, 2 months ago (June 15, 1998)
Published Online 27 years, 2 months ago (June 15, 1998)
Published Print 27 years, 2 months ago (June 15, 1998)
Funders 0

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@article{Seagroves_1998, title={C/EBPβ, but not C/EBPα, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland}, volume={12}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.12.12.1917}, DOI={10.1101/gad.12.12.1917}, number={12}, journal={Genes &amp; Development}, publisher={Cold Spring Harbor Laboratory}, author={Seagroves, Tiffany N. and Krnacik, Susanne and Raught, Brian and Gay, Jason and Burgess-Beusse, Bonnie and Darlington, Gretchen J. and Rosen, Jeffrey M.}, year={1998}, month=jun, pages={1917–1928} }