Differential regulation of gene expression by estrogen in estrogen growth-independent and -dependent MCF-7 human breast cancer cell sublines.
We have examined the ability of estradiol (E2) to regulate the expression of three mRNAs [for pS2, progesterone receptor (PR), and estrogen receptor (ER)], known to be under E2 regulation in the parental E2 growth-responsive MCF-7 cells, in an E2 growth-independent MCF-7 K3), previously isolated from the parental estrogen-dependent MCF-7 K1 human breast cancer cells after long term growth in vitro in the absence of estrogen, acquired estrogen-independent growth in vitro as well as the ability to form tumors in nude mice in vivo without estrogen. We find that the content of pS2 mRNA and the transcription rate of the pS2 gene, while being markedly increased by E2 in MCF-7 K1 cells, are no longer stimulated by E2 in this subline, although protein kinase activators tremendously increase (greater than 10-fold) pS2 mRNA in both K1 and K3 cells. In fact, basal pS2 mRNA levels are elevated 2.8 +/- 0.4-fold in MCF-7 K3 cells, and E2 evokes a concentration-dependent suppression of the pS2 mRNA level. In contrast, PR mRNA in the K3 subline, as in the parental K1 cells, is still up-regulated by E2, and ER mRAN content and the ER mRNA transcription rate are still down-regulated by E2 and show normal E2 dose-response relationships, implying that the ER in this subline is functional. These results demonstrate that the progression to estrogen-independent growth in K3 cells is accompanied by a change in the regulation of some estrogen-induced genes by estrogen. While PR and ER retain normal patterns of regulation by E2, the pS2 gene in the estrogen growth-independent K3 subline is differentially affected and is no longer stimulated by E2. Our data suggest that this altered regulation of the pS2 gene is probably not caused by a defect of the ER or ER regulation in this subline.
Cho
H S
HS
Department of Physiology and Biophysics, University of Illinois College of Medicine, Urbana 61801.
NG
P A
PA
Katzenellenbogen
B S
BS
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics*; D002461:Cell Line, Transformed; D002999:Clone Cells; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000032:analysis*; D011956:Receptors, Cell Surface / Q000235:genetics*; D011959:Receptors, Estradiol / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic
D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011959:Receptors, Estradiol; D011980:Receptors, Progesterone; D004958:Estradiol; D004815:Epidermal Growth Factor; C051781:ICI 164384; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine