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Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668

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Abstract

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/RU58R-1 (RU58R-1) was developed. The RU58R-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 ERα, IGF-I Receptor (IGF-IR) and Bcl-2 were severely reduced, when RU58R-1 cells were cultured with RU 58,668 and the expression of progesterone receptor (PR) was lost. The ERα level increased upon withdrawal of RU 58,668 and the ERα 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 ERα expression or function and we suggest that in the presence of RU 58,668, the RU58R-1 cell line probably uses other mitogenic pathways than the ERα pathway for growth and survival.

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Authors and Affiliations

  1. Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark

    C. K. Fog & A. E. Lykkesfeldt

  2. Department of Surgical Gastroenterology, Hvidovre University Hospital, Denmark

    I. J. Christensen

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  1. C. K. Fog
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  2. I. J. Christensen
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Correspondence to A. E. Lykkesfeldt.

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Fog, C.K., Christensen, I.J. & Lykkesfeldt, A.E. Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668. Breast Cancer Res Treat 91, 133–144 (2005). https://doi.org/10.1007/s10549-004-5871-y

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