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TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells

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Abstract

Response to treatment with the antiestrogen tamoxifen is variable and at least partially due to its highly complex metabolism. Tamoxifen is transformed by polymorphic and inducible cytochrome P450 enzymes to a large number of metabolites with varying biological activities. The estrogen receptor dependent growth inhibitory effect of antiestrogens is mediated by activation of antiproliferative Transforming Growth Factor beta (TGFβ) signal transduction pathways. The aim of the present study was to establish if TGFβ2 or TGFβ receptor II (TβRII), could be used as markers to assess the pharmacological potency of tamoxifen and its metabolites. Consequently, we analyzed the growth inhibitory effect of tamoxifen and its major metabolites and explored whether it correlated with their capacity to induce TGFβ2 and TβRII expression. Human breast cancer cells (MCF-7 and T47D) were treated with tamoxifen and tamoxifen metabolites and mRNA expression of TGFβ2 and TβRII was analyzed by quantitative RT-PCR. Only two metabolites 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen had significant antiproliferative activity and were able to induce TGFβ2 and TβRII. Plasma concentrations of these metabolites are usually very low in patients. However, even minor growth inhibitory effects at concentrations which are below the limit of quantification in plasma samples resulted in clearly discernible effects on expression of TGFβ2 and TβRII. Taken together, our data demonstrate that TGFβ2 and TβRII are very specific and sensitive biomarkers for the antiestrogenic activity of tamoxifen metabolites in breast cancer.

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Acknowledgments

This work was supported by the Robert Bosch Foundation. JK Coller was a recipient of a CJ Martin Postdoctoral Training Fellowship from the National Health and Medical Research Council (NHMRC) of Australia.

We thank Stefanie Laukemann and Tabea Peußer for excellent technical assistance.

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Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, 70376, Germany

    Miriam B. Buck, Thomas E. Mürdter & Michel Eichelbaum

  2. Department of Clinical Chemistry, Robert-Bosch-Hospital, Auerbachstrasse 110, Stuttgart, 70376, Germany

    Miriam B. Buck & Cornelius Knabbe

  3. Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide, 5005, Australia

    Janet K. Coller

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  1. Miriam B. Buck
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  2. Janet K. Coller
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  3. Thomas E. Mürdter
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  4. Michel Eichelbaum
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  5. Cornelius Knabbe
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Correspondence to Cornelius Knabbe.

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Buck, M.B., Coller, J.K., Mürdter, T.E. et al. TGFβ2 and TβRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells. Breast Cancer Res Treat 107, 15–24 (2008). https://doi.org/10.1007/s10549-007-9526-7

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  • DOI: https://doi.org/10.1007/s10549-007-9526-7

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