Immediate early gene X-1 (IEX-1), a hydroxytamoxifen regulated gene with increased stimulation in MCF-7 derived resistant breast cancer cells.
The efficacy of tamoxifen in breast cancer treatment only lasts a few years and the tumor eventually recurs. We performed selective subtractive hybridization to isolate mRNAs that were differentially expressed in MCF-7 derived cells, in which resistance had been induced through long-term culture in the presence of hydroxytamoxifen (OHT). Among the 15 mRNAs found to be overexpressed, we focused on Immediate early gene X-1 (IEX-1) mRNA because of the recognized contribution of its expression to apoptosis or cell cycle progression, depending on the cell type and culture conditions. We observed that IEX-1 expression was stimulated by OHT, that the degree of increase was greater in resistant cells (four-fold versus 1.5-fold) and that this OHT regulation was estrogen receptor dependent. A detailed study of the IEX-1 promoter indicated that it involved NF-kappaB. Our cells were not cross-resistant to faslodex, a pure antiestrogen, which moreover was inefficient in regulating IEX-1 expression. Altogether, our data suggest that the greater IEX-1 expression in OHT resistant cells is related to their ability to grow in the presence of OHT. Knowledge on the capacity of OHT to stimulate gene expression and its NF-kappaB dependence should contribute to a better understanding of tamoxifen pharmacology and allow new drug strategies to be designed that would delay antiestrogen resistance acquisition.
Semlali
Abdelhabib
A
INSERM U.540, 60 Rue de Navacelles, Montpellier 34090, France.
Oliva
Joan
J
Badia
Eric
E
Pons
Michel
M
Duchesne
Marie-Josèphe
MJ
D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000235:genetics*; D003001:Cloning, Molecular; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017781:Genes, Immediate-Early; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; C099815:IER3 protein, human; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene; D013755:Tetradecanoylphorbol Acetate