TY - JOUR
T1 - The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor a for degradation in breast cancer cells
AU - Wu, Xianglin
AU - Hawse, John R.
AU - Subramaniam, Malayannan
AU - Goetz, Matthew P.
AU - Ingle, James N.
AU - Spelsberg, Thomas C.
PY - 2009/3/1
Y1 - 2009/3/1
N2 - 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 F450 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 ERa for degradation by the proteasome in breast cancer cells. Additionally, we show that endoxifen blocks ERa transcriptional activity and inhibits estrogen-induced breast cancer cell proliferation even in the presence of tamoxifen, N-desmethyi-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, wãiua American Association tor cancer Kesearcn.
AB - 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 F450 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 ERa for degradation by the proteasome in breast cancer cells. Additionally, we show that endoxifen blocks ERa transcriptional activity and inhibits estrogen-induced breast cancer cell proliferation even in the presence of tamoxifen, N-desmethyi-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, wãiua American Association tor cancer Kesearcn.
UR - http://www.scopus.com/inward/record.url?scp=62449153701&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62449153701&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-3933
DO - 10.1158/0008-5472.CAN-08-3933
M3 - Article
C2 - 19244106
AN - SCOPUS:62449153701
SN - 0008-5472
VL - 69
SP - 1722
EP - 1727
JO - Cancer research
JF - Cancer research
IS - 5
ER -