A new MCF-7 breast cancer cell line resistant to the arzoxifene metabolite desmethylarzoxifene.
The development of resistance in tamoxifen-treated breast cancer patients and the estrogenic side effects of tamoxifen have lead to the design of many new drugs. The new SERM arzoxifene and its active metabolite desmethylarzoxifene (ARZm) inhibits growth of breast cancer cells and has less estrogenic effects than tamoxifen on gene expression. A cell line with acquired resistance to ARZm (MCF-7/ARZm(R)-1) was established from MCF-7 cells. MCF-7/ARZm(R)-1 cells responded to treatment with tamoxifen and the pure antiestrogen ICI 182,7870. The estrogen receptor alpha (ERalpha) level in MCF-7/ARZm(R)-1 cells was lower than in MCF-7 cells due to a destabilization of the receptor by ARZm. A significant reduction in the mRNA and protein level of some estrogen-regulated genes was observed in MCF-7/ARZm(R)-1 compared to MCF-7. However, both the level of the ERalpha and several ER-regulated gene products increased towards parental MCF-7 level upon withdrawal from ARZm, concomitant with an increase in the sensitivity of MCF-7/ARZm(R)-1 cells to ARZm treatment. These data show that ARZm resistant cells remain sensitive to treatment with both tamoxifen and to ICI 182,780. Furthermore, the partial reversion to ARZm sensitivity upon withdrawal of the SERM suggests that patients may benefit from a rechallenge with ARZm.
Freddie
Cecilie T
CT
Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen Ø, Denmark.
Christensen
Gitte L
GL
Lykkesfeldt
Anne E
AE
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D000077267:Fulvestrant; D051548:Histone Acetyltransferases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D056920:Nuclear Receptor Coactivator 1; D010880:Piperidines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
D047628:Estrogen Receptor alpha; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D013876:Thiophenes; D014157:Transcription Factors; C571169:desmethylarzoxifene; C101118:progesterone receptor A; C097314:progesterone receptor B; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; C115121:LY 353381; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D002402:Cathepsin D