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Priority Reports |
for Degradation in Breast Cancer Cells
Departments of 1Biochemistry and Molecular Biology, and 2Oncology, Mayo Clinic, Rochester, Minnesota
* To whom correspondence should be addressed. E-mail: spelsberg.thomas{at}mayo.edu.
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Abstract |
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Tamoxifen has been the most important therapeutic agent for the treatment of estrogen receptor (ER)-positive breast cancer for the past three decades. Tamoxifen is extensively metabolized by cytochrome P450 enzymes, and recent in vivo studies have shown that women with genetically impaired cytochrome P450 2D6 have reduced production of endoxifen and a higher risk of breast cancer recurrence. Despite these observations, the contribution of endoxifen to the overall drug effectiveness of tamoxifen remains uncertain. Here, we provide novel evidence that endoxifen is a potent antiestrogen that functions in part by targeting ER
for degradation by the proteasome in breast cancer cells. Additionally, we show that endoxifen blocks ER transcriptional activity and inhibits estrogen-induced breast cancer cell proliferation even in the presence of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxytamoxifen. All of the effects of endoxifen are concentration dependent and do not occur at concentrations observed in human CYP2D6 poor metabolizers. These results support the theory that endoxifen is the primary metabolite responsible for the overall effectiveness of tamoxifen in the treatment of ER-positive breast cancer. [Cancer Res 2009;69(5):1722–7
Key Words: breast cancer, endoxifen, tamoxifen, estrogen receptor, estrogen
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