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01-01-2011 | Original Article

Promoter CpG island hypermethylation during breast cancer progression

Authors: So Yeon Park, Hyeong Ju Kwon, Hee Eun Lee, Han Suk Ryu, Sung-Won Kim, Jee Hyun Kim, In Ah Kim, Namhee Jung, Nam-Yun Cho, Gyeong Hoon Kang

Published in: Virchows Archiv | Issue 1/2011

Abstract

This study was designed to evaluate the changes in promoter CpG islands hypermethylation during breast cancer progression from pre-invasive lesions [flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS)] to invasive ductal carcinoma (IDC). We performed MethyLight analysis for the methylation status of 57 promoter CpG island loci in 20 IDCs and their paired normal breast tissues. After selecting 15 CpG island loci showing breast cancer-specific DNA methylation, another set of normal breast tissue (n = 10), ADH/FEA (n = 30), DCIS (n = 35), and IDC (n = 30) of the breast were analyzed for these loci. We found six new methylation markers of breast cancer, namely DLEC1, GRIN2B, HOXA1, MT1G, SFRP4, and TMEFF2, in addition to APC, GSTP1, HOXA10, IGF2, RARB, RASSF1A, RUNX3, SCGB3A1 (HIN-1), and SFRP1. The number of methylated genes increased stepwise from normal breast to ADH/FEA and DCIS, while IDC did not differ from DCIS. Methylation levels and frequencies of APC, DLEC1, HOXA1, and RASSF1A promoter CpG islands were significantly higher in ADH/FEA than in normal breast tissue. GRIN2B, GSTP1, HOXA1, RARB, RUNX3, SFRP1, and TMEFF2 showed higher methylation levels and frequencies in DCIS than in ADH/FEA. DICS and IDC did not differ in the methylation levels or frequencies for most CpG island loci except SFRP1 and HOXA10. Our findings showed that promoter CpG island methylation changed significantly in pre-invasive lesions, and was similar in IDC and DCIS, suggesting that CpG island methylation of tumor-related genes is an early event in breast cancer progression.

Beckmann MW, Niederacher D, Schnürch HG, Gusterson BA, Bender HG (1997) Multistep carcinogenesis of breast cancer and tumour heterogeneity. J Mol Med 75:429–439CrossRefPubMed

Dupont WD, Page DL (1985) Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146–151CrossRefPubMed

Tavassoli FA, Hoefler H, Rosai J, Holland R, Ellis IO, Schnitt SJ, Boecker W, Heywang-Köbrunner SH, Moinfar F, Lakhani SR (2003) Intraductal proliferative lesions. In: Tavassoli FA, Delvilee P (eds) World Health Organization classification of tumors: pathology and genetics of tumours of the breast and female genital organs. IARC, Lyon, pp 63–73

Schnitt SJ, Collins LC (2009) Columnar cell lesions and flat epithelial atypia. In: Biopsy interpretation of the breast. Lippincott Williams & Wilkins, Philadelphia, pp 96–122

Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229PubMed

Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomäki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132–138CrossRefPubMed

Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21:5462–5482CrossRefPubMed

Umbricht CB, Evron E, Gabrielson E, Ferguson A, Marks J, Sukumar S (2001) Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer. Oncogene 20:3348–3353CrossRefPubMed

Lehmann U, Länger F, Feist H, Glöckner S, Hasemeier B, Kreipe H (2002) Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol 160:605–612PubMed

10.

Pasquali L, Bedeir A, Ringquist S, Styche A, Bhargava R, Trucco G (2007) Quantification of CpG island methylation in progressive breast lesions from normal to invasive carcinoma. Cancer Lett 257:136–144CrossRefPubMed

11.

Lee JS, Fackler MJ, Teo WW, Lee JH, Choi C, Park MH, Yoon JH, Zhang Z, Argani P, Sukumar S (2008) Quantitative promoter hypermethylation profiles of ductal carcinoma in situ in North American and Korean women: potential applications for diagnosis. Cancer Biol Ther 7:1398–1406PubMed

12.

Lee JS (2007) GSTP1 promoter hypermethylation is an early event in breast carcinogenesis. Virchows Arch 450:637–642CrossRefPubMed

13.

Liu T, Niu Y, Feng Y, Niu R, Yu Y, Lv A, Yang Y (2008) Methylation of CpG islands of p16(INK4a) and cyclinD1 overexpression associated with progression of intraductal proliferative lesions of the breast. Hum Pathol 39:1637–1646CrossRefPubMed

14.

Lo P, Mehrotra J, D'Costa A, Fackler MJ, Garrett-Mayer E, Argani P, Sukumar S (2006) Epigenetic suppression of secreted frizzled related protein 1 (SFRP1) expression in human breast cancer. Cancer Biol Ther 5:281–286CrossRefPubMed

15.

Hoque MO, Prencipe M, Poeta ML, Barbano R, Valori VM, Copetti M, Gallo AP, Brait M, Maiello E, Apicella A, Rossiello R, Zito F, Stefania T, Paradiso A, Carella M, Dallapiccola B, Murgo R, Carosi I, Bisceglia M, Fazio VM, Sidransky D, Parrella P (2009) Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression. Cancer Epidemiol Biomark Prev 18:2694–2700CrossRef

16.

Subramaniam MM, Chan JY, Soong R, Ito K, Ito Y, Yeoh KG, Salto-Tellez M, Putti TC (2009) RUNX3 inactivation by frequent promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression. Breast Cancer Res Treat 113:113–121CrossRefPubMed

17.

Muggerud AA, Rønneberg JA, Wärnberg F, Botling J, Busato F, Jovanovic J, Solvang H, Bukholm I, Børresen-Dale A, Kristensen VN, Sørlie T, Tost J (2010) Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer. Breast Cancer Res 12:R3CrossRefPubMed

18.

Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, Ehrlich M, Laird PW (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33:6823–6836CrossRefPubMed

19.

Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793CrossRefPubMed

20.

Kang GH, Lee S, Cho N, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW (2008) DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88:161–170CrossRefPubMed

21.

Ogino S, Kawasaki T, Brahmandam M, Cantor M, Kirkner GJ, Spiegelman D, Makrigiorgos GM, Weisenberger DJ, Laird PW, Loda M, Fuchs CS (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217CrossRefPubMed

22.

Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481PubMed

23.

Hyun CL, Lee HE, Kim KS, Kim S, Kim JH, Choe G, Park SY (2008) The effect of chromosome 17 polysomy on HER-2/neu status in breast cancer. J Clin Pathol 61:317–321CrossRefPubMed

24.

Lee JS, Lo P, Fackler MJ, Argani P, Zhang Z, Garrett-Meyer E, Sukumar S (2007) A comparative study of Korean with Caucasian breast cancer reveals frequency of methylation in multiple genes correlates with breast cancer in young, ER, PR-negative breast cancer in Korean women. Cancer Biol Ther 6:1114–1120CrossRefPubMed

25.

Shigematsu H, Suzuki M, Takahashi T, Miyajima K, Toyooka S, Shivapurkar N, Tomlinson GE, Mastrangelo D, Pass HI, Brambilla E, Sathyanarayana UG, Czerniak B, Fujisawa T, Shimizu N, Gazdar A (2005) Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies. Int J Cancer 113:600–604CrossRefPubMed

26.

Bloushtain-Qimron N, Yao J, Snyder EL, Shipitsin M, Campbell LL, Mani SA, Hu M, Chen H, Ustyansky V, Antosiewicz JE, Argani P, Halushka MK, Thomson JA, Pharoah P, Porgador A, Sukumar S, Parsons R, Richardson AL, Stampfer MR, Gelman RS, Nikolskaya T, Nikolsky Y, Polyak K (2008) Cell type-specific DNA methylation patterns in the human breast. Proc Natl Acad Sci USA 105:14076–14081CrossRefPubMed

27.

Krop IE, Sgroi D, Porter DA, Lunetta KL, LeVangie R, Seth P, Kaelin CM, Rhei E, Bosenberg M, Schnitt S, Marks JR, Pagon Z, Belina D, Razumovic J, Polyak K (2001) HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells. Proc Natl Acad Sci USA 98:9796–9801CrossRefPubMed

28.

Kang GH, Lee S, Kim J, Jung H (2003) Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. Lab Invest 83:519–526PubMed

29.

Kang GH, Lee S, Lee HJ, Hwang K (2004) Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. J Pathol 202:233–240CrossRefPubMed

30.

Lee S, Lee HJ, Kim J, Lee H, Jang JJ, Kang GH (2003) Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 163:1371–1378PubMed

31.

Allred DC, Wu Y, Mao S, Nagtegaal ID, Lee S, Perou CM, Mohsin SK, O'Connell P, Tsimelzon A, Medina D (2008) Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution. Clin Cancer Res 14:370–378CrossRefPubMed

32.

Hwang ES, DeVries S, Chew KL, Moore DH 2nd, Kerlikowske K, Thor A, Ljung BM, Waldman FM (2004) Patterns of chromosomal alterations in breast ductal carcinoma in situ. Clin Cancer Res 10:5160–5167CrossRefPubMed

33.

Adeyinka A, Emberley E, Niu Y, Snell L, Murphy LC, Sowter H, Wykoff CC, Harris AL, Watson PH (2002) Analysis of gene expression in ductal carcinoma in situ of the breast. Clin Cancer Res 8:3788–3795PubMed

34.

Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuary P, Payette T, Pistone M, Stecker K, Zhang BM, Zhou YX, Varnholt H, Smith B, Gadd M, Chatfield E, Kessler J, Baer TM, Erlander MG, Sgroi DC (2003) Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA 100:5974–5979CrossRefPubMed

35.

McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning. Cell 68:283–302CrossRefPubMed

36.

Chu MC, Selam FB, Taylor HS (2004) HOXA10 regulates p53 expression and matrigel invasion in human breast cancer cells. Cancer Biol Ther 3:568–572PubMed

37.

Klopocki E, Kristiansen G, Wild PJ, Klaman I, Castanos-Velez E, Singer G, Stöhr R, Simon R, Sauter G, Leibiger H, Essers L, Weber B, Hermann K, Rosenthal A, Hartmann A, Dahl E (2004) Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors. Int J Oncol 25:641–649PubMed

38.

Kwong J, Lee J, Wong K, Zhou X, Wong DTW, Lo K, Welch WR, Berkowitz RS, Mok SC (2006) Candidate tumor-suppressor gene DLEC1 is frequently downregulated by promoter hypermethylation and histone hypoacetylation in human epithelial ovarian cancer. Neoplasia 8:268–278CrossRefPubMed

39.

Seng TJ, Currey N, Cooper WA, Lee C, Chan C, Horvath L, Sutherland RL, Kennedy C, McCaughan B, Kohonen-Corish MRJ (2008) DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma. Br J Cancer 99:375–382CrossRefPubMed

40.

Ying J, Poon FF, Yu J, Geng H, Wong AHY, Qiu G, Goh HK, Rha SY, Tian L, Chan ATC, Sung JJY, Tao Q (2009) DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers. Br J Cancer 100:663–669CrossRefPubMed

41.

Ferrario C, Lavagni P, Gariboldi M, Miranda C, Losa M, Cleris L, Formelli F, Pilotti S, Pierotti MA, Greco A (2008) Metallothionein 1G acts as an oncosupressor in papillary thyroid carcinoma. Lab Invest 88:474–481CrossRefPubMed

42.

Huang Y, de la Chapelle A, Pellegata NS (2003) Hypermethylation, but not LOH, is associated with the low expression of MT1G and CRABP1 in papillary thyroid carcinoma. Int J Cancer 104:735–744CrossRefPubMed

43.

Henrique R, Jerónimo C, Hoque MO, Nomoto S, Carvalho AL, Costa VL, Oliveira J, Teixeira MR, Lopes C, Sidransky D (2005) MT1G hypermethylation is associated with higher tumor stage in prostate cancer. Cancer Epidemiol Biomark Prev 14:1274–1278CrossRef

44.

Dalgin GS, Drever M, Williams T, King T, DeLisi C, Liou LS (2008) Identification of novel epigenetic markers for clear cell renal cell carcinoma. J Urol 180:1126–1130CrossRefPubMed

45.

Feng W, Shen L, Wen S, Rosen DG, Jelinek J, Hu X, Huan S, Huang M, Liu J, Sahin AA, Hunt KK, Bast RC, Shen Y, Issa JJ, Yu Y (2007) Correlation between CpG methylation profiles and hormone receptor status in breast cancers. Breast Cancer Res 9:R57CrossRefPubMed

46.

Sunami E, Shinozaki M, Sim M, Nguyen SL, Vu A, Giuliano AE, Hoon DSB (2008) Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res 10:R46CrossRefPubMed

47.

Lee JS, Fackler MJ, Lee JH, Choi C, Park MH, Yoon JH, Zhang Z, Sukumar S (2010) Basal-like breast cancer displays distinct patterns of promoter methylation. Cancer Biol Ther 9:1017–1024CrossRefPubMed

Title: Promoter CpG island hypermethylation during breast cancer progression
Authors: So Yeon Park
Hyeong Ju Kwon
Hee Eun Lee
Han Suk Ryu
Sung-Won Kim
Jee Hyun Kim
In Ah Kim
Namhee Jung
Nam-Yun Cho
Gyeong Hoon Kang
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 1/2011
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-010-1013-6

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Springer Medicine

Promoter CpG island hypermethylation during breast cancer progression

Abstract

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Springer Medicine

Abstract

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