Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668.
Breast cancer is the most common cancer disease in women in the western world. Tamoxifen has been the standard first line endocrine therapy for patients with estrogen receptor (ER) positive tumors. Unfortunately, almost all patients with advanced disease develop tamoxifen resistance. This has lead to a search for new potent antiestrogens. One of the new compounds under development is the pure antiestrogen RU 58,668. To study the mechanisms behind acquired resistance to RU 58,668, the RU 58,668-resistant cell line MCF-7/RU58(R)-1 (RU58(R)-1) was developed. The RU58(R)-1 cell line was responsive to tamoxifen, but cross-resistant to ICI 182,780 and the estrogen-sensitivity was reduced compared to the parental MCF-7 cell line. The protein levels of ERalpha, IGF-I Receptor (IGF-IR) and Bcl-2 were severely reduced, when RU58(R)-1 cells were cultured with RU 58,668 and the expression of progesterone receptor (PR) was lost. The ERalpha level increased upon withdrawal of RU 58,668 and the ERalpha protein was destabilized by RU 58,668 in both cell lines. Regulation of most of the investigated estrogen-sensitive mRNAs was found to be normal in the resistant cells. The protein levels of IGF-IR, Bcl-2 and the IGF Binding Protein 2 (IGFBP2) reverted towards MCF-7 levels upon RU 58,668 withdrawal, but the resistant phenotype was maintained. Thus, it appears as acquired resistance to RU 58,668 is not a result of loss of the ERalpha expression or function and we suggest that in the presence of RU 58,668, the RU58(R)-1 cell line probably uses other mitogenic pathways than the ERalpha pathway for growth and survival.
Fog
C K
CK
Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Christensen
I J
IJ
Lykkesfeldt
A E
AE
D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000188:drug therapy*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000187:drug effects; D005466:Fluorocarbons
D004958:Estradiol; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; C086511:RU 58668; D005466:Fluorocarbons