Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis.
Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene, PAX2, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.
Wu
Huijian
H
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China.
Chen
Yupeng
Y
Liang
Jing
J
Shi
Bin
B
Wu
Ge
G
Zhang
Ying
Y
Wang
Dan
D
Li
Ruifang
R
Yi
Xia
X
Zhang
Hua
H
Sun
Luyang
L
Shang
Yongfeng
Y
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D051762:PAX2 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000494:pharmacology; D013629:Tamoxifen / Q000009:adverse effects / Q000494:pharmacology*
D047628:Estrogen Receptor alpha; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen