title: Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis.
abstract: SnoN is an important negative regulator of transforming growth factor-beta (TGF-beta) signaling that was originally identified as a transforming oncogene in chicken embryonic fibroblasts. Both pro-oncogenic and antioncogenic activities of SnoN have been reported, but its function in normal epithelial cells has not been defined. In the mouse mammary gland, SnoN is expressed at relatively low levels, but it is transiently upregulated at late gestation before being downregulated during lactation and early involution. To assess the effects of elevated levels of SnoN, we generated transgenic mice expressing a SnoN fragment under the control of the mouse mammary tumor virus promoter. In this model system, SnoN elevation increased side-branching and lobular-alveolar proliferation in virgin glands, while accelerating involution in postlactation glands. Increased proliferation stimulated by SnoN was insufficient to induce mammary tumorigenesis. In contrast, elevated levels of SnoN cooperated with polyoma middle T antigen to accelerate the formation of aggressive multifocal adenocarcinomas and to increase the formation of pulmonary metastases. Our studies define functions of SnoN in mammary epithelial cell proliferation and involution, and provide the first in vivo evidence of a pro-oncogenic role for SnoN in mammalian tumorigenesis.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Nadine S
authors.initials: NS
authors.lastname: Jahchan
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: You
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Kunxin
authors.initials: K
authors.lastname: Luo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007774:Lactation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C060615:SKIL protein, human; D016212:Transforming Growth Factor beta
references.citation: Nat Rev Mol Cell Biol. 2005 Sep;6(9):715-25
references.pmid: 16231422
references.citation: Oncogene. 1993 Feb;8(2):457-66
references.pmid: 8426750
references.citation: J Biol Chem. 1999 Dec 3;274(49):35269-77
references.pmid: 10575014
references.citation: EMBO J. 2000 Apr 17;19(8):1745-54
references.pmid: 10775259
references.citation: J Gen Virol. 1997 Apr;78 ( Pt 4):893-903
references.pmid: 9129663
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4254-8
references.pmid: 7753792
references.citation: Cell Growth Differ. 2002 Mar;13(3):123-30
references.pmid: 11959813
references.citation: EMBO J. 2000 May 15;19(10):2280-91
references.pmid: 10811619
references.citation: Immunol Lett. 2002 Jun 3;82(1-2):85-91
references.pmid: 12008039
references.citation: Cell. 2002 Nov 1;111(3):357-67
references.pmid: 12419246
references.citation: Breast Cancer Res. 2006;8(1):201
references.pmid: 16524451
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: Science. 2002 May 31;296(5573):1646-7
references.pmid: 12040180
references.citation: Cell Growth Differ. 1998 Mar;9(3):229-38
references.pmid: 9543389
references.citation: Mol Cell Biol. 2007 Jan;27(1):324-39
references.pmid: 17074815
references.citation: Science. 1999 Oct 22;286(5440):771-4
references.pmid: 10531062
references.citation: J Cell Sci. 2003 Jul 15;116(Pt 14):2975-86
references.pmid: 12808020
references.citation: Cancer Res. 2003 Aug 15;63(16):5005-10
references.pmid: 12941827
references.citation: Nat Rev Cancer. 2003 Nov;3(11):807-21
references.pmid: 14557817
references.citation: Cancer Res. 2005 Mar 15;65(6):2296-302
references.pmid: 15781643
references.citation: Biochem Biophys Res Commun. 2001 Aug 24;286(3):559-65
references.pmid: 11511096
references.citation: Nucleic Acids Res. 1989 Jul 25;17(14):5489-500
references.pmid: 2762147
references.citation: Nat Rev Cancer. 2006 Jul;6(7):506-20
references.pmid: 16794634
references.citation: Breast Cancer Res. 2006;8(2):203
references.pmid: 16677411
references.citation: Nucleic Acids Res. 1993 Sep 25;21(19):4632-8
references.pmid: 8233802
references.citation: Nat Cell Biol. 2001 Jun;3(6):587-95
references.pmid: 11389444
references.citation: Mol Cell Biol. 2003 Aug;23(15):5446-59
references.pmid: 12861029
references.citation: Cancer Res. 2005 Oct 1;65(19):8617-21
references.pmid: 16204027
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12442-7
references.pmid: 10535941
references.citation: Development. 1991 Nov;113(3):867-78
references.pmid: 1821856
references.citation: Int J Cancer. 2003 Dec 20;107(6):919-28
references.pmid: 14601051
references.citation: Cancer Res. 2005 Jun 1;65(11):4782-8
references.pmid: 15930298
references.citation: Nucleic Acids Res. 1997 Jul 15;25(14):2930-7
references.pmid: 9207045
references.citation: Genes Dev. 1994 Jan;8(1):23-32
references.pmid: 7507074
references.citation: Dev Biol. 2007 Jun 1;306(1):193-207
references.pmid: 17448457
references.citation: Genes Dev. 2001 Nov 1;15(21):2822-36
references.pmid: 11691834
references.citation: Am J Pathol. 2003 Oct;163(4):1539-49
references.pmid: 14507660
references.citation: Cancer Res. 2008 Mar 15;68(6):1809-19
references.pmid: 18339861
references.citation: J Mammary Gland Biol Neoplasia. 2001 Jan;6(1):67-82
references.pmid: 11467453
references.citation: Cell Growth Differ. 2000 Jan;11(1):31-9
references.pmid: 10672901
references.citation: Genes Dev. 1999 Oct 1;13(19):2604-16
references.pmid: 10521404
references.citation: Mol Cell Biol. 2005 Dec;25(24):10731-44
references.pmid: 16314499
references.citation: Genes Dev. 1999 Sep 1;13(17):2196-206
references.pmid: 10485843
references.citation: Mol Cell Biol. 1992 Mar;12(3):954-61
references.pmid: 1312220
references.citation: Genes Dev. 1993 Dec;7(12A):2308-17
references.pmid: 8253379
references.citation: Oncogene. 2006 Jun 8;25(24):3408-23
references.pmid: 16186809
references.citation: EMBO J. 2009 Nov 18;28(22):3500-13
references.pmid: 19745809
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8430-5
references.pmid: 12808151
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12437-42
references.pmid: 16109768
references.citation: Oncogene. 2003 May 19;22(20):3123-9
references.pmid: 12793438