title: Epithelial cell organization suppresses Myc function by attenuating Myc expression.
abstract: c-Myc is an oncogene transcription factor that causes cancer in many settings, including solid tumors that arise in the context of organized tissue structures. Given that disruption of tissue architecture frequently occurs in cancer, there is considerable interest in how cell organization impacts oncogene function. A previous report found that organization of mammary epithelial cells into defined 3-dimensional structures renders them insensitive to the effects of retrovirus-mediated overexpression of Myc, leading to the notion that organization tempers the sensitivity of individual cells to Myc activity. In this article, we report that epithelial cell organization does not profoundly alter Myc activity but, instead, suppresses Myc by modulating its expression. We show that the morphogenesis of mammary epithelial cells into organized acinar structures in vitro is accompanied by widespread changes in gene expression patterns, including a substantial decrease in the expression of Myc. Concomitant with the decrease in endogenous Myc expression, we observe a decrease in transcription from retroviral vectors during morphogenesis and find that Myc transgene expression in acini is much lower than in unorganized cells. This decrease in Myc transgene activity is responsible for the apparent recalcitrance of organized cells to ectopic Myc, as adenovirus-mediated expression of Myc in organized structures potently induces apoptosis. These observations reveal that organization does not alter the inherent response of epithelial cells to Myc and suggest that other tumor suppression mechanisms, apart from structure, antagonize Myc in the development of solid tumors.
authors: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: David R
authors: DR
authors: Simpson
authors: Min
authors: M
authors: Yu
authors: Siyuan
authors: S
authors: Zheng
authors: Zhongming
authors: Z
authors: Zhao
authors: Senthil K
authors: SK
authors: Muthuswamy
authors: William P
authors: WP
authors: Tansey
references: Science. 2000 Jul 7;289(5476):113-6
references: 10884224
references: Int Rev Cytol. 2007;262:253-302
references: 17631191
references: Cell. 2008 Nov 28;135(5):865-78
references: 19041750
references: Mol Cell Biol. 1994 Aug;14(8):5510-22
references: 8035827
references: Genome Biol. 2003;4(10):R69
references: 14519204
references: Nat Cell Biol. 2001 Sep;3(9):785-92
references: 11533657
references: Nat Rev Mol Cell Biol. 2005 Aug;6(8):635-45
references: 16064138
references: Cell. 1998 Aug 7;94(3):363-74
references: 9708738
references: Int J Mol Med. 2002 Feb;9(2):189-96
references: 11786932
references: Cell Cycle. 2007 Feb 15;6(4):418-29
references: 17329972
references: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9
references: 15079075
references: Cell. 2002 Oct 4;111(1):29-40
references: 12372298
references: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9085-90
references: 15150404
references: Cell Cycle. 2006 Feb;5(3):238-41
references: 16434883
references: EMBO Rep. 2005 Feb;6(2):177-83
references: 15678160
references: Cancer Cell. 2008 Dec 9;14(6):447-57
references: 19061836
references: Methods. 2003 Jul;30(3):256-68
references: 12798140
references: Endocr Relat Cancer. 2001 Mar;8(1):47-61
references: 11350726
references: Br J Cancer. 2004 Apr 19;90(8):1612-9
references: 15083194
references: Nature. 2003 Jan 23;421(6921):379-84
references: 12540903
references: Br J Cancer. 1999 Dec;81(8):1385-91
references: 10604737
references: Nat Genet. 2005 Nov;37(11):1289-95
references: 16200064
references: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14694-9
references: 17766436
references: Nucleic Acids Res. 1995 May 25;23(10):1686-90
references: 7784172
references: Nature. 2005 Aug 11;436(7052):807-11
references: 16094360
references: Methods Enzymol. 2006;406:692-701
references: 16472698
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Cell Cycle. 2008 Jan 1;7(1):57-62
references: 18196964
references: Cell Cycle. 2009 Mar 1;8(5):716-24
references: 19221484
references: Mol Cell Biol. 2005 Jun;25(11):4591-601
references: 15899862
references: Mol Cell Biol. 2000 Jan;20(2):556-62
references: 10611234
references: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11400-6
references: 8876147
references: Cell. 1992 Apr 3;69(1):119-28
references: 1555236
references: EMBO J. 1999 Feb 1;18(3):717-26
references: 9927431