Abstract |
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.
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Authors | Abdelhabib Semlali, Joan Oliva, Eric Badia, Michel Pons, Marie-Josèphe Duchesne |
Journal | The Journal of steroid biochemistry and molecular biology
(J Steroid Biochem Mol Biol)
Vol. 88
Issue 3
Pg. 247-59
(Mar 2004)
ISSN: 0960-0760 [Print] England |
PMID | 15120418
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Apoptosis Regulatory Proteins
- DNA Primers
- IER3 protein, human
- Immediate-Early Proteins
- Membrane Proteins
- Neoplasm Proteins
- RNA, Messenger
- Tumor Suppressor Protein p53
- Tamoxifen
- afimoxifene
- Tetradecanoylphorbol Acetate
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Topics |
- Apoptosis Regulatory Proteins
- Base Sequence
- Blotting, Northern
- Breast Neoplasms
(genetics)
- Cloning, Molecular
- DNA Primers
- Gene Expression Regulation, Neoplastic
(drug effects)
- Genes, Immediate-Early
- Humans
- Immediate-Early Proteins
(genetics)
- Membrane Proteins
- Neoplasm Proteins
(genetics)
- Promoter Regions, Genetic
- RNA, Messenger
(genetics)
- Tamoxifen
(analogs & derivatives, pharmacology)
- Tetradecanoylphorbol Acetate
(pharmacology)
- Transcription, Genetic
(physiology)
- Tumor Suppressor Protein p53
(physiology)
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