title: Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells.
abstract: The LIM-only protein, LMO4, is a transcriptional modulator overexpressed in breast cancer. It is oncogenic in murine mammary epithelium and is required for G2/M progression of ErbB2-dependent cells as well as growth and invasion of other breast cancer cell types. However, the mechanisms underlying the oncogenic activity of LMO4 remain unclear. Herein, we show that LMO4 is expressed in all breast cancer subtypes examined and its expression level correlates with the degree of proliferation of such tumours. In addition, we have determined that LMO4 silencing induces G2/M arrest in cells from various breast cancer subtypes, suggesting that LMO4 action in the cell cycle is not restricted to a single breast cancer subtype. This arrest was accompanied by increased cell death, amplification of centrosomes, and formation of abnormal mitotic spindles. Consistent with its ability to positively and negatively regulate the formation of active transcription complexes, overexpression of LMO4 also resulted in an increase in centrosome number. Centrosome amplification has been shown to prolong the G2/M phase of the cell cycle and induce apoptosis; thus, we conclude that supernumerary centrosomes mediate the G2/M arrest and cell death in LMO4-deficient cells. Furthermore, the correlation of centrosome amplification with genomic instability suggests that the impact of dysregulated LMO4 on the centrosome cycle may promote LMO4-induced tumour formation.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106-4965, USA.
authors.forename: Marjorie E
authors.initials: ME
authors.lastname: Montañez-Wiscovich
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Shelton
authors.forename: Darcie D
authors.initials: DD
authors.lastname: Seachrist
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lozada
authors.forename: Emhonta
authors.initials: E
authors.lastname: Johnson
authors.forename: John D
authors.initials: JD
authors.lastname: Miedler
authors.forename: Fadi W
authors.initials: FW
authors.lastname: Abdul-Karim
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Keri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D018385:Centrosome / Q000378:metabolism / Q000473:pathology*; D005260:Female; D019398:Genes, BRCA1; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D008940:Mitotic Index; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011960:Receptors, Estrogen / Q000172:deficiency; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D014157:Transcription Factors
references.citation: Oncogene. 2009 Oct 15;28(41):3608-18
references.pmid: 19648968
references.citation: Nature. 2005 Jul 28;436(7050):518-24
references.pmid: 16049480
references.citation: Mol Cancer. 2008 Dec 22;7:93
references.pmid: 19099607
references.citation: J Clin Invest. 2007 Nov;117(11):3155-63
references.pmid: 17975657
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1978-83
references.pmid: 11830638
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references.pmid: 11553815
references.citation: Oncogene. 2007 Feb 26;26(9):1338-45
references.pmid: 17322919
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6967-72
references.pmid: 12011455
references.citation: Curr Top Microbiol Immunol. 1998;228:75-113
references.pmid: 9401203
references.citation: Oncogene. 2005 Jul 7;24(29):4660-71
references.pmid: 15897907
references.citation: J Histochem Cytochem. 2005 Apr;53(4):475-86
references.pmid: 15805422
references.citation: Biochem Biophys Res Commun. 2006 May 19;343(4):1186-90
references.pmid: 16580634
references.citation: Breast Cancer Res. 2007;9(5):R65
references.pmid: 17910759
references.citation: Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40
references.pmid: 16897746
references.citation: Int J Clin Exp Pathol. 2009;2(5):444-55
references.pmid: 19294003
references.citation: Breast Cancer. 2006;13(2):137-44
references.pmid: 16755107
references.citation: Nature. 2002 Jan 31;415(6871):530-6
references.pmid: 11823860
references.citation: Nature. 2009 Jul 9;460(7252):278-82
references.pmid: 19506557
references.citation: Nat Cell Biol. 2001 May;3(5):E105-8
references.pmid: 11331889
references.citation: J Neurochem. 2008 Oct;107(2):418-31
references.pmid: 18702663
references.citation: Mol Cell. 1999 Mar;3(3):389-95
references.pmid: 10198641
references.citation: Clin Cancer Res. 2005 Apr 15;11(8):2875-8
references.pmid: 15837735
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14452-7
references.pmid: 11734645
references.citation: Oncogene. 2007 Sep 27;26(44):6431-41
references.pmid: 17452977
references.citation: Cancer Res. 2001 Nov 1;61(21):7713-8
references.pmid: 11691781
references.citation: Science. 1999 Feb 5;283(5403):851-4
references.pmid: 9933170
references.citation: Oncogene. 2006 Jan 12;25(2):298-303
references.pmid: 16170356
references.citation: J Biol Chem. 2002 Mar 8;277(10):7849-56
references.pmid: 11751867
references.citation: Cell Mol Life Sci. 2010 Mar;67(6):949-57
references.pmid: 19997957
references.citation: Lancet. 2005 Feb 19-25;365(9460):671-9
references.pmid: 15721472
references.citation: Cell. 2003 Sep 5;114(5):585-98
references.pmid: 13678582
references.citation: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7659-64
references.pmid: 15897450
references.citation: J Biol Chem. 2005 Apr 1;280(13):12747-57
references.pmid: 15677447
references.citation: Cancer Cell. 2006 Feb;9(2):121-32
references.pmid: 16473279
references.citation: Mol Cell. 1999 Oct;4(4):511-8
references.pmid: 10549283
references.citation: Cell Cycle. 2007 Dec 1;6(23):2944-52
references.pmid: 18000399
references.citation: Cancer Cell. 2006 Dec;10(6):515-27
references.pmid: 17157791
references.citation: Oncogene. 2006 May 11;25(20):2920-30
references.pmid: 16331278
references.citation: Cancer Res. 2005 Nov 15;65(22):10594-601
references.pmid: 16288053
references.citation: Blood. 1999 Feb 15;93(4):1390-8
references.pmid: 9949183
references.citation: Breast Cancer Res Treat. 2002 Sep;75(1):25-34
references.pmid: 12500932
references.citation: Genes Chromosomes Cancer. 2002 Nov;35(3):193-203
references.pmid: 12353262
references.citation: Mol Cell Biol. 1998 Jan;18(1):546-57
references.pmid: 9418901
references.citation: Cancer Cell. 2006 Dec;10(6):529-41
references.pmid: 17157792
references.citation: Cancer Res. 2006 Apr 15;66(8):4020-9
references.pmid: 16618721
references.citation: Genes Dev. 1998 Sep 1;12(17):2651-7
references.pmid: 9732263
references.citation: N Engl J Med. 2002 Dec 19;347(25):1999-2009
references.pmid: 12490681
references.citation: Cancer Res. 2002 Mar 1;62(5):1256-60
references.pmid: 11888886
references.citation: Cell. 1993 Nov 19;75(4):805-16
references.pmid: 8242751
references.citation: Neoplasia. 2004 Jan-Feb;6(1):1-6
references.pmid: 15068665
references.citation: Oncogene. 2004 Feb 26;23(8):1507-13
references.pmid: 14676840
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17108-13
references.pmid: 15563594