title: Three-dimensional nuclear telomere architecture changes during endometrial carcinoma development.
abstract: Endometrioid or type-I endometrial carcinoma (EC) develops from hyperproliferative glandular pathologies. Inactivation of the tumor suppressor gene PTEN is frequently associated with type-I EC. Using a previously characterized Pten heterozygous (Pten+/-) mouse model, this study investigates the three-dimensional (3D) telomere profiles during progression from hyperplastic lesions to EC to test the hypothesis that altered 3D telomere profiles can be detected prior to Pten loss in early hyperproliferative lesions. We used immunohistochemistry and 3D-telomere fluorescent in-situ hybridization to investigate Pten expression, telomere length and signal distribution, average number and spatial distribution of telomeres and formation of telomere aggregates in uterine glandular epithelial cells from wildtype and Pten+/- mice. Pten showed nuclear and cytoplasmic localization in WT, predominantly cytoplasmic staining in simple hyperplasia (SH) and was markedly reduced in atypical hyperplasia (AH). Telomere length in glandular epithelial cells does not shorten with age. The average number of telomeres per nucleus was not different in WT and Pten+/- mice indicating the lack of substantial numeric chromosome aberrations during EC development. We observed telomere aggregates in lesions of AH and EC. SH lesions in Pten+/- mice differed from normal glandular epithelium by an increased relative number of shorter telomeres and by a telomere signal distribution indicative of a heterogeneous cell population. Our study revealed that alterations in the nuclear 3D telomere architecture are present in early proliferative lesions of mouse uterine tissues indicative of EC development. The changes in telomere length distribution and nuclear signal distribution precede the loss of Pten.
authors: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
authors: Adrian
authors: A
authors: Danescu
authors: Sandra
authors: S
authors: Herrero Gonzalez
authors: Antonio
authors: A
authors: Di Cristofano
authors: Sabine
authors: S
authors: Mai
authors: Sabine
authors: S
authors: Hombach-Klonisch
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016615:Telomere / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure*
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references: Crit Rev Eukaryot Gene Expr. 2000;10(2):179-212
references: 11186332
references: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1563-8
references: 9990064
references: Cytometry A. 2009 May;75(5):428-39
references: 19097172
references: Curr Biol. 1998 Oct 22;8(21):1169-78
references: 9799734
references: Am J Pathol. 2003 Jul;163(1):295-301
references: 12819034
references: Am J Surg Pathol. 1999 Sep;23(9):1102-8
references: 10478671
references: Cancer Res. 1998 Aug 1;58(15):3254-8
references: 9699651
references: J Pathol. 2006 Oct;210(2):214-23
references: 16909412
references: Hum Mutat. 2000;16(2):109-22
references: 10923032
references: Cancer. 2002 May 1;94(9):2369-79
references: 12015762
references: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9613-8
references: 15983382
references: BMC Biol. 2004 Jun 03;2:12
references: 15176976
references: Cancer Res. 2006 Apr 1;66(7):3375-80
references: 16585156
references: Diagn Cytopathol. 2013 Mar;41(3):212-7
references: 21965052
references: Cell Cycle. 2009 Jul 15;8(14):2198-210
references: 19502790
references: J Natl Cancer Inst. 2000 Jun 7;92(11):924-30
references: 10841828
references: Cell. 2001 Sep 21;106(6):661-73
references: 11572773
references: Nat Genet. 2004 Sep;36(9):932-4
references: 15340427
references: Nucleic Acids Res. 1997 Aug 1;25(15):3051-8
references: 9224604
references: Nature. 2007 Jun 21;447(7147):924-31
references: 17581575
references: J Clin Invest. 2012 Apr;122(4):1138-43
references: 22466654
references: Cell. 2007 Jan 12;128(1):141-56
references: 17218261
references: Mod Pathol. 2005 Mar;18(3):324-30
references: 15529181
references: Cell Cycle. 2005 Oct;4(10):1327-31
references: 16205113
references: Biochem J. 2008 Jun 1;412(2):331-8
references: 18307411
references: Haematologica. 2010 Dec;95(12):2038-46
references: 20823137
references: Nat Rev Genet. 2012 Jan 24;13(3):189-203
references: 22269907
references: Am J Pathol. 2004 Mar;164(3):925-35
references: 14982846
references: Eur J Cell Biol. 2004 Dec;83(11-12):681-90
references: 15679112
references: Ann Anat. 2010 Sep 20;192(5):292-301
references: 20800459
references: J Clin Endocrinol Metab. 2000 Jun;85(6):2334-8
references: 10852473
references: Semin Cancer Biol. 2011 Dec;21(6):349-53
references: 22015685
references: J Microsc. 2001 Nov;204(Pt 2):99-107
references: 11737543
references: Semin Oncol. 2007 Oct;34(5):428-34
references: 17920899
references: Eur J Hum Genet. 2008 Nov;16(11):1289-300
references: 18781191
references: Am J Clin Oncol. 2010 Aug;33(4):341-5
references: 19884805
references: Nat Genet. 1998 Aug;19(4):348-55
references: 9697695
references: Cancer. 2008 Oct 15;113(8):2073-81
references: 18720479
references: Cell. 2007 Jan 12;128(1):129-39
references: 17218260
references: Cancer Res. 2000 Jul 1;60(13):3605-11
references: 10910075
references: Nat Rev Genet. 2010 May;11(5):319-30
references: 20351727
references: Neoplasia. 2010 Feb;12(2):183-91
references: 20126476
references: Cancer Res. 2008 Jul 15;68(14):6014-20
references: 18632658
references: J Cell Sci. 2008 Feb 1;121(Pt 3):249-53
references: 18216329
references: Cold Spring Harb Symp Quant Biol. 1993;58:777-92
references: 7525149
references: J Biol Chem. 2010 Jan 8;285(2):1457-67
references: 19864690
references: Cell. 2007 Jan 12;128(1):157-70
references: 17218262
references: Cytometry A. 2011 Feb;79(2):159-66
references: 21265009
references: J Clin Oncol. 2010 Feb 10;28(5):788-92
references: 20065186
references: Gynecol Oncol. 1989 Oct;35(1):50-4
references: 2792902
references: Oncogene. 2002 Jan 21;21(4):532-40
references: 11850778
references: Curr Opin Obstet Gynecol. 2002 Feb;14(1):59-65
references: 11801878
references: Int J Gynecol Cancer. 2011 Nov;21(8):1343-9
references: 21989218
references: BMC Cell Biol. 2010 Dec 14;11:99
references: 21144060
references: Nature. 1989 Jan 26;337(6205):331-7
references: 2463488
references: Hum Cell. 1995 Mar;8(1):43-8
references: 7669752
references: Cancer Res. 2002 Nov 15;62(22):6405-9
references: 12438224
references: Clin Cancer Res. 2012 Jun 15;18(12):3293-304
references: 22539801
references: Virchows Arch. 2004 Mar;444(3):213-23
references: 14747944
references: Hum Mol Genet. 2002 Feb 15;11(4):445-50
references: 11854177
references: Gynecol Oncol. 2011 Jul;122(1):79-82
references: 21492921
references: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references: 20610543
references: Cancer Lett. 2006 Sep 28;241(2):184-96
references: 16412571
references: Eur J Cancer. 2012 Feb;48(3):305-10
references: 22133571
references: Cell. 2000 Feb 18;100(4):387-90
references: 10693755
references: Cancer Res. 2003 Jan 15;63(2):282-6
references: 12543774
references: J Cell Sci. 2008 Dec 15;121(Pt 24):4018-28
references: 19056671
references: Clin Cancer Res. 2001 Apr;7(4):892-5
references: 11309338
references: Am J Obstet Gynecol. 1972 Dec 15;114(8):1012-9
references: 4673779
references: Genes Dev. 2007 Dec 1;21(23):3027-43
references: 18056419
references: Int J Cell Biol. 2012;2012:379685
references: 22536248
references: Cell. 1999 May 14;97(4):503-14
references: 10338214
references: Am J Pathol. 2008 Aug;173(2):536-44
references: 18599611
references: J Cell Biochem. 2010 Apr 15;109(6):1095-102
references: 20127711
references: Nature. 2005 Sep 1;437(7055):94-100
references: 16136133
references: Cytometry A. 2005 Oct;67(2):144-50
references: 16163697
references: Mutat Res. 2012 Feb 1;730(1-2):28-36
references: 21575645
references: Am J Pathol. 2002 Nov;161(5):1541-7
references: 12414502
references: J Environ Pathol Toxicol Oncol. 2003;22(3):179-99
references: 14529093
references: Ann Anat. 2010 Sep 20;192(5):302-8
references: 20810259
references: Genetics. 1941 Mar;26(2):234-82
references: 17247004
references: Cytometry. 1999 Aug 1;36(4):267-78
references: 10404142
references: Clin Cancer Res. 2004 May 15;10(10):3317-26
references: 15161685
references: J Cell Biochem. 2006 Apr 1;97(5):904-15
references: 16408280