Regular Article

British Journal of Cancer (2001) 85, 69–73. doi:10.1054/bjoc.2001.1853 www.bjcancer.com
Published online 3 July 2001

Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers

Z Jin1, G Tamura1, T Tsuchiya1, K Sakata1, M Kashiwaba2, M Osakabe1 and T Motoyama1

  1. 1Department of Pathology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
  2. 2Department of Surgery, Iwate Medical University of Medicine, Morioka, 020-8505, Japan

Received 20 November 2000; Revised 15 March 2001; Accepted 27 March 2001.

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Abstract

Similar to findings in colorectal cancers, it has been suggested that disruption of the adenomatous polyposis coli (APC)/beta-catenin pathway may be involved in breast carcinogenesis. However, somatic mutations of APC and beta- catenin are infrequently reported in breast cancers, in contrast to findings in colorectal cancers. To further explore the role of the APC/beta-catenin pathway in breast carcinogenesis, we investigated the status of APC gene promoter methylation in primary breast cancers and in their non-cancerous breast tissue counterparts, as well as mutations of the APC and beta- catenin genes. Hypermethylation of the APC promoter CpG island was detected in 18 of 50 (36%) primary breast cancers and in none of 21 non-cancerous breast tissue samples, although no mutations of the APC and beta- catenin were found. No significant associations between APC promoter hypermethylation and patient age, lymph node metastasis, oestrogen and progesterone receptor status, size, stage or histological type of tumour were observed. These results indicate that APC promoter CpG island hypermethylation is a cancer-specific change and may be a more common mechanism of inactivation of this tumour suppressor gene in primary breast cancers than previously suspected. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

hypermethylation, APC, breast cancer, methylation-specific PCR

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References

  1. Bui TD, Rankin J, Smith K, Huguet EL, Ruben S, Strachan T, Harris AL and Lindsay S (1997) A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas. Oncogene 14: 1249–1253 | Article | PubMed | ISI | ChemPort |
  2. Candidus S, Bischoff P, Becker KF and Hofler H (1996) No evidence for mutations in the alpha-and beta-catenin genes in human gastric and breast carcinomas. Cancer Res 56: 49–52 | PubMed | ISI | ChemPort |
  3. Clark SJ, Harrison J, Paul CL and Frommer M (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22: 2990–2997 | Article | PubMed | ISI | ChemPort |
  4. Dale TC, Weber-Hall SJ, Smith K, Huguet EL, Jayatilake H, Gusterson BA, Shuttleworth G, O'Hare M and Harris AL (1996) Compartment switching of WNT-2 expression in human breast tumors. Cancer Res 56: 4320–4323 | PubMed | ISI | ChemPort |
  5. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB and Herman JG (2000a) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92: 564–569 | Article | PubMed | ChemPort |
  6. Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Gonzalez S, Tarafa G, Sidransky D, Meltzer SJ, Baylin SB and Herman JG (2000b) Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 60: 4366–4371 | PubMed | ISI | ChemPort |
  7. Gonzalgo ML, Bender CM, You EH, Glendening JM, Flores JF, Walker GJ, Hayward NK, Jones PA and Fountain JW (1997) Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches for methylation analysis of primary tumors. Cancer Res 57: 5336–5347 | PubMed | ISI | ChemPort |
  8. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE and Baylin SB (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55: 5195–5199 | PubMed | ISI | ChemPort |
  9. Hart MJ, de los Santos R, Albert IN, Rubinfeld B and Polakis P (1998) Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 8: 573–581 | Article | PubMed | ISI | ChemPort |
  10. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM and Baylin SB (1994) Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91: 9700–9704 | PubMed | ChemPort |
  11. Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D and Baylin SB (1995) Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530 | PubMed | ISI | ChemPort |
  12. Hiltunen MO, Alhonen L, Koistinaho J, Myohanen S, Paakkonen M, Marin S, Kosma VM and Janne J (1997) Hypermethylation of the APC (adenomatous polyposis coli) gene promoter region in human colorectal carcinoma. Int J Cancer 70: 644–648 | Article | PubMed | ISI | ChemPort |
  13. Ho KY, Kalle WH, Lo TH, Lam WY and Tang CM (1999) Reduced expression of APC and DCC gene protein in breast cancer. Histopathology 35: 249–256 | Article | PubMed |
  14. Issa JP (2000) CpG-island methylation in aging and cancer. Curr Top Microbiol Immunol 249: 101–118 | PubMed | ISI | ChemPort |
  15. Jones PA and Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21: 163–167 | Article | PubMed | ISI | ChemPort |
  16. Jonsson M, Borg A, Nilbert M and Andersson T (2000) Involvement of adenomatous polyposis coli (APC) /beta-catenin signalling in human breast cancer. Eur J Cancer 36: 242–248 | Article | PubMed | ISI | ChemPort |
  17. Kashiwaba M, Tamura G and Ishida M (1994) Aberrations of the APC gene in primary breast carcinoma. J Cancer Res Clin Oncol 120: 727–731 | Article | PubMed | ISI | ChemPort |
  18. Kinzler KW and Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87: 159–170 | Article | PubMed | ISI | ChemPort |
  19. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/-colon carcinoma. Science 275: 1784–1787 | Article | PubMed | ISI | ChemPort |
  20. Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A and Peltomaki P (2000) Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 156: 1773–1779 | PubMed | ISI | ChemPort |
  21. Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG and Hung MC (2000) beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A 97: 4262–4266 | PubMed |
  22. Mancini DN, Rodenhiser DI, Ainsworth PJ, O'Malley FP, Singh SM, Xing W and Archer TK (1998) CpG methylation within the 5' regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene 16: 1161–1169 | Article | PubMed | ISI | ChemPort |
  23. Medeiros AC, Nagai MA, Neto MM and Brentani RR (1994) Loss of heterozygosity affecting the APC and MCC genetic loci in patients with primary breast carcinomas. Cancer Epidemiol Biomarkers Prev 3: 331–333 | PubMed | ISI | ChemPort |
  24. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275: 1787–1790 | Article | PubMed | ISI | ChemPort |
  25. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K and Akiyama T (1998) Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3 beta and APC and reduces the beta-catenin level. Genes Cells 3: 395–403 | Article | PubMed | ISI | ChemPort |
  26. Park WS, Oh RR, Park JY, Lee SH, Shin MS, Kim YS, Kim SY, Lee HK, Kim PJ, Oh ST, Yoo NJ and Lee JY (1999) Frequent somatic mutations of the beta-catenin gene in intestinal-type gastric cancer. Cancer Res 59: 4257–4260 | PubMed | ISI | ChemPort |
  27. Rice JC, Massey-Brown KS and Futscher BW (1998) Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17: 1807–1812 | Article | PubMed | ISI | ChemPort |
  28. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S and Polakis P (1993) Association of the APC gene product with beta-catenin. Science 262: 1731–1734 | Article | PubMed | ISI | ChemPort |
  29. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E and Polakis P (1997) Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 275: 1790–1792 | Article | PubMed | ISI | ChemPort |
  30. Sambrook J, Frisch EF and Maniatis T (1989). Molecular cloning: a laboratory manual, 2nd edn, Cold Spring Harbor Laboratory, New York
  31. Schlosshauer PW, Brown SA, Eisinger K, Yan Q, Guglielminetti ER, Parsons R, Ellenson LH and Kitajewski J (2000) APC truncation and increased beta-catenin levels in a human breast cancer cell line. Carcinogenesis 21: 1453–1456 | Article | PubMed | ISI | ChemPort |
  32. Sparks AB, Morin PJ, Vogelstein B and Kinzler KW (1998) Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 58: 1130–1134 | PubMed | ISI | ChemPort |
  33. Su LK, Vogelstein B and Kinzler KW (1993) Association of the APC tumor suppressor protein with catenins. Science 262: 1734–1737 | Article | PubMed | ISI | ChemPort |
  34. Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM, Kong D, Smolinski KN, Wilson KT, James SP, Silverberg SG, Nishizuka S, Terashima M, Motoyama T and Meltzer SJ (2000) E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst 92: 569–573 | Article | PubMed | ChemPort |
  35. Thompson AM, Morris RG, Wallace M, Wyllie AH, Steel CM and Carter DC (1993) Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. Br J Cancer 68: 64–68 | PubMed | ISI | ChemPort |
  36. Tsuchiya T, Tamura G, Sato K, Endoh Y, Sakata K, Jin Z, Motoyama T, Usuba O, Kimura W, Nishizuka S, Wilson KT, James SP, Yin J, Fleisher AS, Zou T, Silverberg SG, Kong D and Meltzer SJ (2000) Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia. Oncogene 19: 3642–3646 | Article | PubMed | ISI | ChemPort |