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Tamoxifen metabolite endoxifen interferes with the polyamine pathway in breast cancer

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Abstract

Tamoxifen is the most widely used drug to treat women with estrogen receptor α (ERα)-positive breast cancer. Endoxifen is recognized as the active metabolite of tamoxifen in humans. We studied endoxifen effects on ERα-positive MCF-7 breast cancer cells. Estradiol increased the proliferation of MCF-7 cells by two- to threefold and endoxifen suppressed its effects. Endoxifen suppressed c-myc, c-fos and Tff1 oncogene expression, as revealed by RT-PCR. Estradiol increased the activity of ornithine decarboxylase (ODC) and adenosyl methioninedecarboxylase (AdoMetDC), whereas endoxifen suppressed these enzyme activities. Endoxifen increased activities of spermine oxidase (SMO) and acetyl polyamine oxidase (APAO) significantly, and reduced the levels of putrescine and spermidine. These data suggest a possible mechanism for the antiestrogenic effects of tamoxifen/endoxifen, involving the stimulation of polyamine oxidase enzymes. Therefore, SMO and APAO stimulation might be useful biomarkers for the efficacy of endoxifen treatment of breast cancer.

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Abbreviations

AdoMetDC:

S-adenosyl-l-methionine decarboxylase

APAO:

Acetyl polyamine oxidase

CYP:

Cytochrome P450

DCC:

Dextran coated charcoal

DMEM:

Dulbecco’s modified Eagle’s medium

Endo:

Endoxifen

E2 :

Estradiol

ER:

Estrogen receptor

FBS:

Fetal bovine serum

4HT:

4-Hydroxytamoxifen

ODC:

Ornithine decarboxylase

qPCR:

Quantitative polymerase chain reaction

SMO:

Spermine oxidase

SSAT:

Spermidine/spermine N1-acetyltransferase

STR:

Short tandem repeat

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Acknowledgments

We express our sincere thanks to Dr. Abdul Fauq of the Mayo Clinic Florida for supplying the purified form of (Z)-endoxifen for this work. This work was supported, in part, by a grant (PC28-11) from the Foundation of the University of Medicine and Dentistry of New Jersey (Currently NJ Health Foundation) to TJT. Work in the laboratories of TAK and MTH was supported by the strategic funding of the University of Eastern Finland and grants from the Academy of Finland (Grant no. 266196).

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  1. Thresia Thomas

    Present address: , 40 Caldwell Drive, Princeton, NJ, 08540, USA

Authors and Affiliations

  1. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

    T. J. Thomas & Shali John

  2. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    T. J. Thomas & Thresia Thomas

  3. Formerly Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

    Thresia Thomas

  4. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Hui-Chen Hsu & PingAr Yang

  5. School of Pharmacy, University of Eastern Finland, Biocenter Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Tuomo A. Keinänen & Mervi T. Hyvönen

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Thomas, T.J., Thomas, T., John, S. et al. Tamoxifen metabolite endoxifen interferes with the polyamine pathway in breast cancer. Amino Acids 48, 2293–2302 (2016). https://doi.org/10.1007/s00726-016-2300-6

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