Variant estrogen receptor-alpha messenger RNA expression in hormone-independent human breast cancer cells.
T5-PRF cells are insensitive to the growth-stimulatory effects of estrogen while still retaining expression of estrogen receptor-alpha (ER-alpha). In the apparent absence of ligand, T5-PRF cells have a 3. 6+/-0.5 (s.e.m.)-fold increased basal ER-alpha activity and elevated basal progesterone receptor levels compared with the parent, estrogen-sensitive, T5 cells. Long-range ER-alpha reverse transcription-PCR was performed to characterize variant ER-alpha mRNA expression in the two cell lines. An increased relative expression of an exon 3/4-deleted ER-alpha mRNA variant was found in T5-PRF. Recombinant expression of this ER-alpha variant resulted in significantly increased estrogen responsiveness, as well as a trend to increased basal ligand-independent activity when expressed with wild-type ER-alpha in ER-negative cell lines, as well as significantly increasing both ligand-independent and estrogen-induced ER-alpha transcriptional activity when expressed in parental T5 cells. These results suggest a role for altered variant ER-alpha in ligand-independent activation of ER-alpha which may contribute to hormone independence in breast tumors.
Coutts
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AS
Department of Biochemistry and Molecular Biology, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W3.
Leygue
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E
Murphy
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LC
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology*; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008970:Molecular Weight; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers / Q000235:genetics
D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004247:DNA