TY - JOUR
T1 - Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer
AU - Martens, John W.M.
AU - Nimmrich, Inko
AU - Koenig, Thomas
AU - Look, Maxime P.
AU - Harbeck, Nadia
AU - Model, Fabian
AU - Kluth, Antje
AU - Bolt-De Vries, Joan
AU - Sieuwerts, Anieta M.
AU - Portengen, Henk
AU - Meijer-Van Gelder, Marion E.
AU - Piepenbrock, Christian
AU - Olek, Alexander
AU - Höfler, Heinz
AU - Kiechle, Marion
AU - Klijn, Jan G.M.
AU - Schmitt, Manfred
AU - Maier, Sabine
AU - Foekens, John A.
N1 - Funding Information:
The senior author would like to thank CSIRO Complex Systems Science initiative for funding.
PY - 2005/5/15
Y1 - 2005/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=20144365156&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-0064
DO - 10.1158/0008-5472.CAN-05-0064
M3 - Article
C2 - 15899800
AN - SCOPUS:20144365156
SN - 0008-5472
VL - 65
SP - 4101
EP - 4107
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -