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Expression Analysis of DNA Methyltransferases 1, 3A, and 3B in Sporadic Breast Carcinomas

Laboratoire d’Oncogénétique–Institut National de la Santé et de la Recherche Médicale E0017 Centre René Huguenin, F-92211 St-Cloud [I. G., S. T., R. L., I. B.], and Laboratoire de Génétique Moléculaire–Unité Propre de Recherche et d’Enseignement Supérieur EA 3618, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes–Paris V, F-75006 Paris [I. B.], France

Purpose: Three genes, namely DNA methyltransferase (DNMT) 1, DNMT3A, and DNMT3B, coding for DNMTs that affect promoter methylation status are thought to play an important role in the development of cancers. Little is known of the biological and clinical significance of these genes in human breast cancer.

Experimental Design: We used real-time reverse transcription-PCR assays to quantify the mRNA expression of the three DNMT genes in a series of 130 breast cancer patients. We also sought relationships between mRNA levels of the DNMTs and those of 20 target genes involved in the DNMT pathway (subgroup of 46 breast tumors).

Results: The DNMT3B gene showed the highest range of expression (81.8 compared with 16.6 and 14 for DNMT1 and DNMT3A, respectively). DNMT3B was overexpressed in 30% of the patients (5.4 and 3.1% for DNMT1 and DNMT3A, respectively). DNMT3B overexpression was significantly related to Scarff, Bloom, and Richardson histopathological grade III (P = 0.002), ER negativity (P = 0.0015), and strong MKI67 expression (P = 3 x 10^-6). In univariate analysis, DNMT3B overexpression was associated with poor relapse-free survival in the subgroup of patients who received adjuvant hormone therapy (with or without chemotherapy; P = 0.0064). Although the poor prognosis associated with DNMT3B overexpression was confirmed by univariate analysis in an independent series of 98 postmenopausal women exclusively treated with adjuvant tamoxifen therapy (P = 0.0036), DNMT3B expression status did not persist as an independent prognostic factor in multivariate analysis.

Conclusions: Although we failed to identify underexpression of specific target genes associated with DNMT increasing expression, the frequent overexpression of DNMT3B in this breast tumor series points to DNMT3B as a potential new therapeutic target in breast cancer.

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