Oncogenomics

Oncogene (2004) 23, 1481–1488. doi:10.1038/sj.onc.1207263 Published online 8 December 2003

Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors

Fabrício F Costa1, Newton V Verbisck1, Anna Christina M Salim1, Daniela F Ierardi1, Lilian C Pires1, Regina M Sasahara2, Mari C Sogayar2, Silvio M Zanata3, Alan Mackay4, Michael O'Hare4, Fernando Soares5, Andrew JG Simpson1 and Anamaria A Camargo1

  1. 1Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, SP, Brazil
  2. 2Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil
  3. 3Laboratório de Neurobiologia, Universidade Federal do Paraná, PR, Brazil
  4. 4Breast Cancer Laboratory, Ludwig Institute for Cancer Research, University College, England
  5. 5Departamento de Patologia, Hospital ACCamargo, SP, Brazil

Correspondence: AA Camargo, Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research (LICR), Rua Professor Antônio Prudente 109, 4th floor, São Paulo,SP 01509-010, Brazil. E-mail: anamaria@compbio.ludwig.org.br

Received 7 May 2003; Accepted 10 October 2003; Published online 8 December 2003.

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Abstract

Altered cell adhesion is causally involved in tumor progression, and the identification of novel adhesion molecules altered in tumors is crucial for our understanding of tumor biology and for the development of new prognostic and therapeutic strategies. Here, we provide evidence for the epigenetic downregulation in breast tumors of the A Desintegrin And Metalloprotease domain 23 gene (ADAM 23), a member of a new family of surface molecules with roles in cell–cell adhesion and/or cell–matrix interactions. We examined the mRNA expression and methylation status of the 5' upstream region of the ADAM23 gene in different breast tumor cell lines as well as in primary breast tumors. We found ADAM23 5' hypermethylation in eight out of 12 (66.7%) tumor cell lines and in nine out of 13 (69.2%) primary tumors. Promoter hypermethylation was strongly associated with reductions in both mRNA and protein expression, with a threshold of 40–60% of modified CpG dinucleotides being required for the complete silencing of ADAM23 mRNA expression. Treatment of MCF-7 and SKBR-3 cell lines with 5'-Aza-2'-deoxycytidine led to a reactivation of ADAM23 mRNA expression and a marked decrease in the methylation level. It is worth noting that primary breast tumors with a more advanced grade showed a higher degree of methylation, suggesting that the adhesion molecule ADAM23 may be downregulated during the progression of breast cancer.

Keywords:

ADAM23, methylation, cell adhesion, downregulation, breast tumor

Abbreviations:

ADAM, A Desintegrin And Metalloprotease domain; MDC, Metalloprotease/Disintegrin/Cysteine rich; TACE, TNF-alpha converting enzyme; TNF-alpha, tumor necrosis factor-alpha; CAM, cell adhesion molecule; 5'-Aza-dCR, 5'-Aza-2'-deoxycytidine