Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen.
We have generated DNA methylation profiles of 148 human breast tumors and found significant differences in hormone receptor (HR) status between clusters of DNA methylation profiles. Of 35 DNA methylation markers analyzed, the ESR1 gene, encoding estrogen receptor alpha, proved to be the best predictor of progesterone receptor status, whereas methylation of the PGR gene, encoding progesterone receptor, was the best predictor of estrogen receptor status. ESR1 methylation outperformed HR status as a predictor of clinical response in patients treated with the antiestrogen tamoxifen, whereas promoter methylation of the CYP1B1 gene, encoding a tamoxifen- and estradiol-metabolizing cytochrome p450, predicted response differentially in tamoxifen-treated and nontamoxifen-treated patients. High levels of promoter methylation of the ARHI gene, encoding a RAS-related small G-protein, were strongly predictive of good survival in patients who had not received tamoxifen therapy. Our results reveal an as yet unrecognized degree of interaction between DNA methylation and HR biology in breast cancer cells and suggest potentially clinically useful novel DNA methylation predictors of response to hormonal and non-hormonal breast cancer therapy.
Widschwendter
Martin
M
Department of Urology, University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California, 90089-9176, USA.
Siegmund
Kimberly D
KD
Müller
Hannes M
HM
Fiegl
Heidi
H
Marth
Christian
C
Müller-Holzner
Elisabeth
E
Jones
Peter A
PA
Laird
Peter W
PW
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D065633:Cytochrome P-450 CYP1B1; D019175:DNA Methylation; D047628:Estrogen Receptor alpha; D006801:Humans; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics*; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000235:genetics
D018931:Antineoplastic Agents, Hormonal; C117386:DIRAS3 protein, human; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D020741:rho GTP-Binding Proteins