Acquired tamoxifen resistance: Correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytainoxifen

C. Kent Osborne, Ester Coronado, D. Craig Allred, Valerie Wiebe, Michael DeGregorio

Research output: Contribution to journalArticle

216 Scopus citations

Abstract

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-hydroxytamoxifen 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.

Original languageEnglish (US)
Pages (from-to)1477-1482
Number of pages6
JournalJournal of the National Cancer Institute
Volume83
Issue number20
StatePublished - Oct 16 1991
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

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