title: Embryonic stem cells are redirected to non-tumorigenic epithelial cell fate by interaction with the mammary microenvironment.
abstract: Experiments were conducted to redirect mouse Embryonic Stem (ES) cells from a tumorigenic phenotype to a normal mammary epithelial phenotype in vivo. Mixing LacZ-labeled ES cells with normal mouse mammary epithelial cells at ratios of 1:5 and 1:50 in phosphate buffered saline and immediately inoculating them into epithelium-divested mammary fat pads of immune-compromised mice accomplished this. Our results indicate that tumorigenesis occurs only when normal mammary ductal growth is not achieved in the inoculated fat pads. When normal mammary gland growth occurs, we find ES cells (LacZ+) progeny interspersed with normal mammary cell progeny in the mammary epithelial structures. We demonstrate that these progeny, marked by LacZ expression, differentiate into multiple epithelial subtypes including steroid receptor positive luminal cells and myoepithelial cells indicating that the ES cells are capable of epithelial multipotency in this context but do not form teratomas. In addition, in secondary transplants, ES cell progeny proliferate, contribute apparently normal mammary progeny, maintain their multipotency and do not produce teratomas.
authors: Mammary Stem Cell Biology Section, Cell and Cancer Biology Branch, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Corinne A
authors: CA
authors: Boulanger
authors: Robert D
authors: RD
authors: Bruno
authors: David L
authors: DL
authors: Mack
authors: Monica
authors: M
authors: Gonzales
authors: Nadia P
authors: NP
authors: Castro
authors: David S
authors: DS
authors: Salomon
authors: Gilbert H
authors: GH
authors: Smith
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D060833:Cellular Microenvironment / Q000187:drug effects / Q000235:genetics; D002678:Chimera; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000473:pathology*; D051379:Mice; D011980:Receptors, Progesterone / Q000378:metabolism; D013724:Teratoma / Q000201:enzymology / Q000473:pathology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000199:Actins; D047628:Estrogen Receptor alpha; D053605:Leukemia Inhibitory Factor; D011980:Receptors, Progesterone; C544013:alpha-smooth muscle actin, mouse; D001616:beta-Galactosidase
references: Science. 1976 Dec 24;194(4272):1439-41
references: 827022
references: Oncogene. 2011 Feb 10;30(6):679-89
references: 20890308
references: Stem Cells Dev. 2012 Apr 10;21(6):948-54
references: 21649558
references: Science. 1965 Aug 6;149(3684):634-6
references: 14331183
references: FASEB J. 2005 Aug;19(10):1341-3
references: 15928194
references: Stem Cells Dev. 2011 Jun;20(6):1053-62
references: 20874104
references: Nat Genet. 1999 Jan;21(1):70-1
references: 9916792
references: Differentiation. 2003 Jan;71(1):1-17
references: 12558599
references: Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Jul;86(1 Pt 2):016309
references: 23005527
references: Curr Top Dev Biol. 1967;2:223-46
references: 5634085
references: Breast Cancer Res Treat. 1996;39(1):21-31
references: 8738603
references: Nature. 2006 Feb 23;439(7079):993-7
references: 16395311
references: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14891-6
references: 18809919
references: Development. 1987 Jul;100(3):421-30
references: 3308404
references: Oncogene. 2005 Jan 20;24(4):552-60
references: 15580303
references: J Virol. 1991 Nov;65(11):6365-70
references: 1656102
references: In Vitro. 1971 Nov-Dec;7(3):140-5
references: 5163648
references: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3871-6
references: 17360445
references: Breast Cancer Res. 2011 Aug 11;13(4):R79
references: 21834968
references: Stem Cells. 2005 Feb;23(2):166-85
references: 15671141
references: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94
references: 9108056
references: J Cell Biol. 2012 May 28;197(5):575-84
references: 22641343
references: Genes Dev. 1991 Sep;5(9):1513-23
references: 1653172
references: Cancer Res. 1959 Jun;19(5):515-20
references: 13663040
references: Bibl Haematol. 1975;(40):271-2
references: 1164399
references: Cancer Res. 2010 Aug 1;70(15):6336-43
references: 20647316
references: Nat Biotechnol. 2007 Jul;25(7):803-16
references: 17572666