© 1991 by Oxford University Press
Journal of the National Cancer Institute, Vol. 83, No. 20, 1477-1482,
October 16, 1991
© 1991 Oxford University Press
Acquired Tamoxifen Resistance: Correlation With Reduced Breast Tumor Levels of Tamoxifen and Isomerization of Trans-4-Hydroxytamoxifen
Department of Medicine, Division of Oncology, University of Texas Health Science Center San Antonio, Tex.
Department of Pathology University of Texas Health Science Center San Antonio, Tex.
Department of Research, Cancer Therapy and Research Center, San Antonio, Tex.
*Correspondence to: C. Kent Osborne, M.D., Department of Medicine, Division of Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284.
Acquired tamoxifen resistance represents a major cause of treatment failure in breast cancer. We implanted estrogen receptor-positive MCF-7 human breast cancer cells in athymic nude BALB/c mice as a model to study in vivo acquired tamoxifen resistance. After 4–6 months of tumor growth suppression by trans-tamoxifen, tumor progression was observed despite continued tamoxifen administration. Acquired resistance was not due to loss of estrogen receptors, to alterations in serum or tumor estrogen levels, or to changes in tamoxifen or its major metabolites in serum. Tamoxifen-resistant tumors remained estrogen dependent in vivo. However, resistance was also associated with the ability of tamoxifen to stimulate tumor growth. Resistant tumors were characterized by markedly lower intracellular tamoxifen levels and by isomerization of the potent antiestrogenic metabolite trans-4-hydroxy-tamoxifen to the less potent cis isomer. Metabolic tolerance, as manifested by alterations in cellular concentrations of tamoxifen and its metabolites, may thus be one mechanism for acquired tamoxifen resistance in breast cancer. [J Natl Cancer Inst 83: 1477–1482, 1991]
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