Mitogenic estrogen metabolites alter the expression of 17beta-estradiol-regulated proteins including heat shock proteins in human MCF-7 breast cancer cells.
Estrogen metabolites are carcinogenic. The comparative mitogenic activities of 17b-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 16a-hydroxyestrone (16a-OHE1) and 2-methoxyestradiol (2-ME), were determined in estrogen receptor(ER)-positive MCF-7 human breast cancer cells. Each of the E2 metabolites caused proliferation of the MCF-7 cells, but only E2 and 16a-OHE1 induced a greater than 20-fold increases in transcripts of the progesterone receptor (PR) gene, a classical ER-mediated gene. This suggests that the mitogenic action of E2 and 16a-OHE1 could result from their effects on gene expression via the ER. E2 metabolites altered the expression of E2-regulated proteins including heat shock proteins (Hsps). 16a-OHE1 and 2-ME as well as E2 increased levels of Hsp56, Hsp60, Hsp90a and Hsp110 transcripts, and the patterns of these inductions resembled that of PR. Hsp56 and Hsp60 protein levels were increased by all the E2 metabolites. Levels of the transcripts of 3 E2-upregulated proteins (XTP3-transactivated protein A, protein disulfide isomerase-associated 4 protein and stathmin 1) and an E2-downregulated protein (aminoacylase 1) were also affected by the E2 metabolites. These results suggest that the altered expression of Hsps (especially Hsp56 and Hsp60) by E2 metabolites such as E2, 16a-OHE1 and 2-ME could be closely linked to their mitogenic action.
Kim
Seong Hwan
SH
Laboratory of Chemical Genomics, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea. hwan@krict.re.kr
Lee
Su-Ui
SU
Kim
Myung Hee
MH
Kim
Bum Tae
BT
Min
Yong Ki
YK
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008934:Mitogens / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050777:Stathmin / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018834:Chaperonin 60; D018841:HSP90 Heat-Shock Proteins; D008934:Mitogens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C493995:STMN1 protein, human; D050777:Stathmin; D004958:Estradiol; D000581:Amidohydrolases; C019672:aminoacylase I; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4