Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors.
OBJECTIVE
We have shown previously that acquired tamoxifen resistance in an in vivo experimental model is associated with reduced tamoxifen accumulation, isomerization of trans-4-hydroxytamoxifen, and tamoxifen-stimulated tumor growth. The purpose of this study is to isolate and verify the presence of estrogenic tamoxifen metabolites in human breast tumors using high-performance liquid chromatography (HPLC) and mass-spectrometry (MS) techniques.


METHODS
In the present study, we used HPLC and MS to identify the presence of estrogenic metabolites in tumor samples excised from athymic nude mice and in human breast tumors isolated from patients receiving adjuvant tamoxifen therapy.


RESULTS
We identified the presence of metabolite E, a known estrogenic metabolite of tamoxifen, in tamoxifen-resistant MCF-7 human breast tumors implanted in athymic nude mice, as well as in tumors from patients with clinical resistance. Additionally, we separated another estrogenic metabolite, bisphenol, by HPLC, and this was also tentatively confirmed by MS analysis.


CONCLUSIONS
These data suggest that cellular tamoxifen metabolism to estrogenic metabolites may in part contribute to stimulating the growth of hormone-responsive breast tumors following prolonged exposure to tamoxifen. Further evaluation of the relationship between cellular metabolism and acquired tamoxifen resistance is warranted.
Wiebe
V J
VJ
Cancer Therapy and Research Center, San Antonio, TX.
Osborne
C K
CK
McGuire
W L
WL
DeGregorio
M W
MW
D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D004351:Drug Resistance; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000032:analysis*
D013629:Tamoxifen