Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer.

Abstract

To understand the biological basis of resistance to endocrine therapy is of utmost importance in patients with steroid hormone receptor-positive breast cancer. Not only will this allow us prediction of therapy success, it may also lead to novel therapies for patients resistant to current endocrine therapy. DNA methylation in the promoter regions of genes is a prominent epigenetic gene silencing mechanism that contributes to breast cancer biology. In the current study, we investigated whether promoter DNA methylation could be associated with resistance to endocrine therapy in patients with recurrent breast cancer. Using a microarray-based technology, the promoter DNA methylation status of 117 candidate genes was studied in a cohort of 200 steroid hormone receptor-positive tumors of patients who received the antiestrogen tamoxifen as first-line treatment for recurrent breast cancer. Of the genes analyzed, the promoter DNA methylation status of 10 genes was significantly associated with clinical outcome of tamoxifen therapy. The association of the promoter hypermethylation of the strongest marker, phosphoserine aminotransferase (PSAT1) with favorable clinical outcome was confirmed by an independent quantitative DNA methylation detection method. Furthermore, the extent of DNA methylation of PSAT1 was inversely associated with its expression at the mRNA level. Finally, also at the mRNA level, PSAT1 was a predictor of tamoxifen therapy response. Concluding, our work indicates that promoter hypermethylation and mRNA expression of PSAT1 are indicators of response to tamoxifen-based endocrine therapy in steroid hormone receptor-positive patients with recurrent breast cancer.

• Authors: John W M Martens, Inko Nimmrich, Thomas Koenig, Maxime P Look, Nadia Harbeck, Fabian Model, Antje Kluth, Joan Bolt-de Vries, Anieta M Sieuwerts, Henk Portengen, Marion E Meijer-Van Gelder, Christian Piepenbrock, Alexander Olek, Heinz Höfler, Marion Kiechle, Jan G M Klijn, Manfred Schmitt, Sabine Maier, John A Foekens
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 10 Pg. 4101-17 (May 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15899800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• RNA, Messenger
• Tamoxifen
• Transaminases
• phosphoserine aminotransferase

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Hormonal (therapeutic use)
• Breast Neoplasms (drug therapy, enzymology, genetics)
• CpG Islands (genetics)
• DNA Methylation
• Female
• Humans
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, enzymology, genetics)
• Polymerase Chain Reaction
• Predictive Value of Tests
• Promoter Regions, Genetic
• RNA, Messenger (genetics, metabolism)
• Tamoxifen (therapeutic use)
• Transaminases (genetics)