A new MCF-7 breast cancer cell line resistant to the arzoxifene metabolite desmethylarzoxifene

TY - JOUR

T1 - A new MCF-7 breast cancer cell line resistant to the arzoxifene metabolite desmethylarzoxifene

AU - Freddie, Cecilie T

AU - Christensen, Gitte Lund

AU - Lykkesfeldt, Anne E

PY - 2004/5/31

Y1 - 2004/5/31

N2 - 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.

AB - 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.

KW - Breast Neoplasms

KW - Cathepsin D

KW - Cell Division

KW - Cell Line, Tumor

KW - Drug Resistance, Neoplasm

KW - Estradiol

KW - Estrogen Receptor alpha

KW - Histone Acetyltransferases

KW - Humans

KW - Nuclear Proteins

KW - Nuclear Receptor Co-Repressor 1

KW - Nuclear Receptor Coactivator 1

KW - Piperidines

KW - Proto-Oncogene Proteins c-bcl-2

KW - RNA, Messenger

KW - Receptors, Progesterone

KW - Repressor Proteins

KW - Tamoxifen

KW - Thiophenes

KW - Transcription Factors

U2 - 10.1016/j.mce.2004.03.005

DO - 10.1016/j.mce.2004.03.005

M3 - Journal article

C2 - 15196704

SN - 0303-7207

VL - 220

SP - 97

EP - 107

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

IS - 1-2

ER -