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  • Original Paper
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Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers

Abstract

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-α (ERα). Previous investigation suggests that methylation of CpGs within the ERα promoter mediates repression of gene expression in some ERα-negative breast cancers. To determine if methylation of CpGs within the ERα promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ERα gene in 40 ERα-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P<0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ERα gene in BRCA1-linked breast cancers.

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References

  • Archey WB, Sweet MP, Alig GC, Arrick BA . 1999 Cancer Res. 59: 2292–2296

  • Barrett-Lee PJ, Travers MT, McClellend RA, Luqmani Y, Coombes RC . 1987 Cancer Res. 47: 6653–6659

  • Berns EMJJ, Van Staveren IL, Verhoog L, Van de Ouweland AMW, Meijer-van Gelder M, Meijers-Heijboer H, Portengen H, Foekens JA, Dorssers LCJ, Klijn JGM . 2001 Br. J. Cancer 85: 538–545

  • Catteau A, Harris WH, Xu CF, Solomon E . 1999 Oncogene 18: 1957–1965

  • Cervoni N, Szyf M . 2001 J. Biol. Chem. 44: 40778–40787

  • Cornelis RS, Neuhausen SL, Johansson O, Arason A, Kelsell D, Ponder BAJ, Tonin P, Hamann U, Lindblom A, Lalle P, Longy M, Olah E, Scherneck S, Bignon Y-J, Sobol H, Chang-Claude J, Larsson C, Spurr N, Borg Å, Barkardottir RB, Narod S, Devilee P Breast Cancer Linkage Consortium. 1995 Genes Chromosomes Cancer 13: 203–210

  • DeConinck EC, McPherson LA, Weigel RJ . 1995 Mol. Cell. Biol. 15: 2191–2196

  • Dobosy JR, Selker EU . 2001 Cell. Mol. Life Sci. 58: 721–727

  • Ferguson AT, Lapidus RG, Baylin SB, Davidson NE . 1995 Cancer Res. 55: 2279–2283

  • Hedenfalk I, Duggan D, Chen YD, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg Å, Trent J . 2001 N. Engl. J. Med. 344: 539–548

  • Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826

  • Iwase H, Omoto Y, Iwata H, Toyama T, Hara Y, Ando Y, Ito Y, Fujii Y, Kobayashi S . 1999 Br. J. Cancer 80: 1982–1986

  • Jóhannsson OT, Idvall I, Anderson C, Borg Å, Barkardóttir RB, Egilsson V, Olsson H . 1997 Eur. J. Cancer 33: 362–371

  • Karp SE, Tonin PN, Bégin LR, Martinez JJ, Zhang JC, Pollak MN, Foulkes WD . 1997 Cancer 80: 435–441

  • Lapidus RG, Ferguson AT, Ottaviano YL, Parl FF, Smith HS, Weitzman SA, Baylin SB, Issa PJ, Davidson NE . 1996 Clin. Cancer Res. 2: 805–810

  • Lapidus RG, Nass SJ, Butash KA, Parl FF, Weitzman SA, Graff JG, Herman JG, Davidson NE . 1998 Cancer Res. 58: 2515–2519

  • Loman N, Johannsson O, Bendahl PO, Borg Å, Fernö M, Olsson H . 1998 Cancer 83: 310–319

  • McPherson LA, Baichwal VR, Weigel RJ . 1997 Proc. Natl. Acad. Sci. USA 94: 4342–4347

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S . 1994 Science 266: 66–71

  • Neuhausen SL, Marshall CJ . 1994 Cancer Res. 54: 6069–6072

  • Penolazzi L, Lambertini E, Aguiari G, Del Senno L, Piva R . 2000 Biochim. Biophys. Acta Gene Struct Expression 1492: 560–567

  • Piva R, Rimondi AP, Hanau S, Maestri I, Alvisi A, Kumar VL, Del Senno L . 1990 Br. J. Cancer 61: 270–275

  • Tang Z, Treilleux I, Brown M . 1997 Mol. Cell. Biol. 17: 1274–1280

  • Tomlinson GE, Chen TTL, Stastny VA, Virmani AK, Spillman MA, Tonk V, Blum JL, Schneider NR, Wistuba II, Shay JW, Minna JD, Gazdar AF . 1998 Cancer Res. 58: 3237–3242

  • Van't Veer LJ, Dai HY, Van de Vijver MJ, He YDD, Hart AAM, Mao M, Peterse HL, Van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH . 2002 Nature 415: 530–536

  • Vaziri SAJ, Krumroy LM, Elson P, Budd GT, Darlington G, Myles J, Tubbs RR, Casey G . 2001 Clin. Cancer Res. 7: 1937–1945

  • Wang Q, Zhang HT, Fishel R, Greene MI . 2000 Oncogene 19: 6152–6158

  • Welcsh PL, Owens KN, King MC . 2000 Trends Genet. 16: 69–74

  • Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ . 1999 Nature Genet. 21: 236–240

  • Yaich L, Dupont WD, Cavener DR, Parl FF . 1992 Cancer Res. 52: 77–83

  • Yang XW, Ferguson AT, Nass SJ, Phillips DL, Butash KA, Wang SM, Herman JG, Davidson NE . 2000 Cancer Res. 60: 6890–6894

  • Yarden RI, Brody LC . 1999 Proc. Natl. Acad. Sci. USA 96: 4983–4988

  • Yoshikawa K, Honda K, Inamoto T, Shinohara H, Yamauchi A, Suga K, Okuyama T, Shimada T, Kodama H, Noguchi S, Gazdar AF, Yamaoka Y, Takahashi R . 1999 Clin. Cancer Res. 5: 1249–1261

  • Zheng L, Li S, Boyer TG, Lee W-H . 2000 Oncogene 19: 6159–6175

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Acknowledgements

This work was supported by grants CA77772 from the National Cancer Institute and DAMD17-99-1-9166 from the Department of Defense Breast Cancer Research Program. Dr WB Archey was supported in part by the Rosaline Borrison Memorial Fellowship.

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Correspondence to Bradley A Arrick.

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Archey, W., McEachern, K., Robson, M. et al. Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers. Oncogene 21, 7034–7041 (2002). https://doi.org/10.1038/sj.onc.1205844

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