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Open Access 01-11-2012 | Preclinical Study

Prognostic value of LINE-1 retrotransposon expression and its subcellular localization in breast cancer

Authors: Long Chen, Jane E. Dahlstrom, Arin Chandra, Philip Board, Danny Rangasamy

Published in: Breast Cancer Research and Treatment | Issue 1/2012

Abstract

Long interspersed nuclear element 1 (L1) belongs to a family of retrotransposons. Expression of the normally repressed L1 retrotransposons has been shown to induce genome instability by creating DNA double-stranded breaks and chromosomal rearrangements through the process of retrotransposition. At present, little is known about the expression of L1-encoded ORF1p and ORF2p which are indispensable for its retrotransposition activity. Given its potentially harmful effects on the genome, we investigated the implications of both ORF1p and ORF2p expression and their subcellular localization in a range of breast cancer cell lines and breast tumor tissues including 15 normal breast tissues, 25 fibroadenomas, 25 ductal carcinomas in situ (DCIS), and 95 invasive cancers. Clinicopathologic parameters and survival outcomes were investigated in association with the cytoplasmic and nuclear expression of ORF1p and ORF2p using univariate and multivariate analysis. High cytoplasmic expression of ORF1p and ORF2p was seen in DCIS tumors, but they were not related with survival outcome. The majority of invasive cancers were found to express both ORF1p and ORF2p in the cytoplasm, while nuclear expression was also seen in a subclass of those invasive cancers in the range of 28–31 %. Tumors with high nuclear expression of ORF1p and ORF2p were more significantly associated with lymph node metastasis (p = 0.001) and the worst patient survival (p < 0.0001) than those with cytoplasmic expression. This is the first study examining the effects of both ORF1p and ORF2p expression in breast cancer tissues. Our observation shows altered expression patterns of ORF1p and ORF2p within invasive cancers, which are related to differences in overall patient survival. The differing patterns of both cytoplasmic and nuclear ORF1p and ORF2p expression indicate that further studies of the biology and function of L1 retrotransposons are required in breast cancer.

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Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428. doi:10.1038/nrg816 PubMed

Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21(35):5400–5413. doi:10.1038/sj.onc.1205651 PubMedCrossRef

Chalitchagorn K, Shuangshoti S, Hourpai N, Kongruttanachok N, Tangkijvanich P, Thong-ngam D, Voravud N, Sriuranpong V, Mutirangura A (2004) Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis. Oncogene 23(54):8841–8846. doi:10.1038/sj.onc.1208137 PubMedCrossRef

Phokaew C, Kowudtitham S, Subbalekha K, Shuangshoti S, Mutirangura A (2008) LINE-1 methylation patterns of different loci in normal and cancerous cells. Nucleic Acids Res 36(17):5704–5712PubMedCrossRef

Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32(3):e38. doi:10.1093/nar/gnh032 PubMedCrossRef

Cruickshanks HA, Tufarelli C (2009) Isolation of cancer-specific chimeric transcripts induced by hypomethylation of the LINE-1 antisense promoter. Genomics 94(6):397–406. doi:10.1016/j.ygeno.2009.08.013 PubMedCrossRef

Beck CR, Collier P, Macfarlane C, Malig M, Kidd JM, Eichler EE, Badge RM, Moran JV (2010) LINE-1 retrotransposition activity in human genomes. Cell 141(7):1159–1170. doi:10.1016/j.cell.2010.05.021 PubMedCrossRef

Sassaman DM, Dombroski BA, Moran JV, Kimberland ML, Naas TP, DeBerardinis RJ, Gabriel A, Swergold GD, Kazazian HH Jr. (1997) Many human L1 elements are capable of retrotransposition. Nat Genet 16(1):37–43. doi:10.1038/ng0597-37 PubMedCrossRef

Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV, Kazazian HH Jr. (2003) Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci USA 100(9):5280–5285PubMedCrossRef

10.

Martin SL, Bushman FD (2001) Nucleic acid chaperone activity of the ORF1 protein from the mouse LINE-1 retrotransposon. Mol Cell Biol 21(2):467–475. doi:10.1128/MCB.21.2.467-475.2001 PubMedCrossRef

11.

Mathias SL, Scott AF, Kazazian HH Jr., Boeke JD, Gabriel A (1991) Reverse transcriptase encoded by a human transposable element. Science 254(5039):1808–1810PubMedCrossRef

12.

Feng Q, Moran JV, Kazazian HH Jr., Boeke JD (1996) Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87(5):905–916PubMedCrossRef

13.

Symer DE, Connelly C, Szak ST, Caputo EM, Cost GJ, Parmigiani G, Boeke JD (2002) Human l1 retrotransposition is associated with genetic instability in vivo. Cell 110(3):327–338PubMedCrossRef

14.

Gilbert N, Lutz-Prigge S, Moran JV (2002) Genomic deletions created upon LINE-1 retrotransposition. Cell 110(3):315–325PubMedCrossRef

15.

Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10(10):691–703PubMedCrossRef

16.

Iskow RC, McCabe MT, Mills RE, Torene S, Pittard WS, Neuwald AF, Van Meir EG, Vertino PM, Devine SE (2010) Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141(7):1253–1261. doi:10.1016/j.cell.2010.05.020 PubMedCrossRef

17.

Garcia-Perez JL, Morell M, Scheys JO, Kulpa DA, Morell S, Carter CC, Hammer GD, Collins KL, O’Shea KS, Menendez P, Moran JV (2010) Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466(7307):769–773. doi:10.1038/nature09209 PubMedCrossRef

18.

Chen L, Dahlstrom JE, Lee SH, Rangasamy D (2012) Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation. Epigenetics 7(7):758–771

19.

Rangasamy D (2010) An S/MAR-based L1 retrotransposition cassette mediates sustained levels of insertional mutagenesis without suffering from epigenetic silencing of DNA methylation. Epigenetics 5(7):601–611PubMedCrossRef

20.

Craft PS, Zhang Y, Brogan J, Tait N, Buckingham JM (2000) Implementing clinical practice guidelines: a community-based audit of breast cancer treatment. Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group. Med J Aust 172(5):213–216PubMed

21.

Winters ZE, Hunt NC, Bradburn MJ, Royds JA, Turley H, Harris AL, Norbury CJ (2001) Subcellular localisation of cyclin B, Cdc2 and p21(WAF1/CIP1) in breast cancer. Association with prognosis. Eur J Cancer 37(18):2405–2412PubMedCrossRef

22.

Leibold DM, Swergold GD, Singer MF, Thayer RE, Dombroski BA, Fanning TG (1990) Translation of LINE-1 DNA elements in vitro and in human cells. Proc Natl Acad Sci USA 87(18):6990–6994PubMedCrossRef

23.

Dmitriev SE, Andreev DE, Terenin IM, Olovnikov IA, Prassolov VS, Merrick WC, Shatsky IN (2007) Efficient translation initiation directed by the 900-nucleotide-long and GC-rich 5′ untranslated region of the human retrotransposon LINE-1 mRNA is strictly cap dependent rather than internal ribosome entry site mediated. Mol Cell Biol 27(13):4685–4697PubMedCrossRef

24.

Ergun S, Buschmann C, Heukeshoven J, Dammann K, Schnieders F, Lauke H, Chalajour F, Kilic N, Stratling WH, Schumann GG (2004) Cell type-specific expression of LINE-1 open reading frames 1 and 2 in fetal and adult human tissues. J Biol Chem 279(26):27753–27763. doi:10.1074/jbc.M312985200 PubMedCrossRef

25.

Harris CR, Normart R, Yang Q, Stevenson E, Haffty BG, Ganesan S, Cordon-Cardo C, Levine AJ, Tang LH (2010) Association of nuclear localization of a long interspersed nuclear element-1 protein in breast tumors with poor prognostic outcomes. Genes Cancer 1(2):115–124. doi:10.1177/1947601909360812 PubMedCrossRef

26.

Bratthauer GL, Cardiff RD, Fanning TG (1994) Expression of LINE-1 retrotransposons in human breast cancer. Cancer 73(9):2333–2336PubMedCrossRef

27.

Asch HL, Eliacin E, Fanning TG, Connolly JL, Bratthauer G, Asch BB (1996) Comparative expression of the LINE-1 p40 protein in human breast carcinomas and normal breast tissues. Oncol Res 8(6):239–247PubMed

28.

Banaz-Yasar F, Steffen G, Hauschild J, Bongartz BM, Schumann GG, Ergun S (2010) LINE-1 retrotransposition events affect endothelial proliferation and migration. Histochem Cell Biol 134(6):581–589. doi:10.1007/s00418-010-0758-y PubMedCrossRef

29.

Doucet AJ, Hulme AE, Sahinovic E, Kulpa DA, Moldovan JB, Kopera HC, Athanikar JN, Hasnaoui M, Bucheton A, Moran JV, Gilbert N (2010) Characterization of LINE-1 ribonucleoprotein particles. PLoS Genet. doi:10.1371/journal.pgen.1001150

30.

Belgnaoui SM, Gosden RG, Semmes OJ, Haoudi A (2006) Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells. Cancer Cell Int 6:13. doi:10.1186/1475-2867-6-13 PubMedCrossRef

31.

Ellsworth DL, Ellsworth RE, Liebman MN, Hooke JA, Shriver CD (2004) Genomic instability in histologically normal breast tissues: implications for carcinogenesis. Lancet Oncol 5(12):753–758PubMedCrossRef

32.

Saito K, Kawakami K, Matsumoto I, Oda M, Watanabe G, Minamoto T (2010) Long interspersed nuclear element 1 hypomethylation is a marker of poor prognosis in stage IA non-small cell lung cancer. Clin Cancer Res 16(8):2418–2426. doi:10.1158/1078-0432.CCR-09-2819 PubMedCrossRef

33.

van Hoesel AQ, van de Velde CJ, Kuppen PJ, Liefers GJ, Putter H, Sato Y, Elashoff DA, Turner RR, Shamonki JM, de Kruijf EM, van Nes JG, Giuliano AE, Hoon DS (2012) Hypomethylation of LINE-1 in primary tumor has poor prognosis in young breast cancer patients: a retrospective cohort study. Breast Cancer Res Treat. doi:10.1007/s10549-012-2038-0

34.

Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, Osborne CK, Tormey DC, McGuire WL (1992) Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 23(9):974–979PubMedCrossRef

35.

Dobrescu A, Chang M, Kirtani V, Turi GK, Hennawy R, Hindenburg AA (2011) Study of estrogen receptor and progesterone receptor expression in breast ductal carcinoma in situ by immunohistochemical staining in ER/PgR-negative invasive breast cancer. ISRN Oncol 2011:673790. doi:10.5402/2011/673790 PubMed

36.

Podo F, Buydens LM, Degani H, Hilhorst R, Klipp E, Gribbestad IS, Van Huffel S, van Laarhoven HW, Luts J, Monleon D, Postma GJ, Schneiderhan-Marra N, Santoro F, Wouters H, Russnes HG, Sorlie T, Tagliabue E, Borresen-Dale AL (2010) Triple-negative breast cancer: present challenges and new perspectives. Mol Oncol 4(3):209–229. doi:10.1016/j.molonc.2010.04.006 PubMedCrossRef

37.

Park WS, Oh RR, Park JY, Kim PJ, Shin MS, Lee JH, Kim HS, Lee SH, Kim SY, Park YG, An WG, Jang JJ, Yoo NJ, Lee JY (2001) Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma. J Pathol 193(4):483–490PubMedCrossRef

38.

Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R, Mattei E, Serafino A, Cassano A, Sinibaldi-Vallebona P, Garaci E, Barone C, Spadafora C (2005) Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene 24(24):3923–3931. doi:10.1038/sj.onc.1208562 PubMedCrossRef

39.

Han JS, Boeke JD (2005) LINE-1 retrotransposons: modulators of quantity and quality of mammalian gene expression? BioEssays 27(8):775–784. doi:10.1002/bies.20257 PubMedCrossRef

Title: Prognostic value of LINE-1 retrotransposon expression and its subcellular localization in breast cancer
Authors: Long Chen
Jane E. Dahlstrom
Arin Chandra
Philip Board
Danny Rangasamy
Publication date: 01-11-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2246-7

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