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Immediate early gene X-1 (IEX-1), a hydroxytamoxifen regulated gene with increased stimulation in MCF-7 derived resistant breast cancer cells.

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.
AuthorsAbdelhabib Semlali, Joan Oliva, Eric Badia, Michel Pons, Marie-Josèphe Duchesne
JournalThe 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
PMID15120418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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