© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 10, 806-812,
May 19, 1993
© 1993 Oxford University Press
Investigation of the Mechanism of Tamoxifen-Stimulated Breast Tumor Growth With Nonisomerizable Analogues of Tamoxifen and Metabolites
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center Madison
Chiros Limited, Cambridge Science Park Cambridge, England
Correspondence to: V. Craig Jordan, Ph.D., D.Sc., Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, 600 Highland Ave., Madison, WI 53792.
Background: The nonsteroidal antiestrogen tamoxifen (TAM) is the front-line endocrine treatment for breast cancer, but disease recurrence is common. Treatment failure may occur because tumors become insensitive to TAM. Alternatively, resistance may occur because tumors become stimulated rather than inhibited by TAM. TAM-stimulated growth of MCF-7 human breast tumors has been observed in athymic mice after prolonged treatment with TAM. Purpose: Our purpose was to examine the mechanism of treatment failure by determining whether TAM-stimulated tumors acquire the ability to excrete TAM and its antiestrogenic metabolites or to convert them to estrogenic compounds with weakened antiestrogenic activity. Methods: We used high-pressure liquid chromatography to quantitate TAM and its metabolites in serum and tumors from ovariectomized athymic mice and in MCF-7 cells grown in vitro. We treated tumor-bearing mice with subcutaneous sustained-release preparations of estradiol, TAM, or a nonisomerizable (fixed-ring) analogue and then assessed the activity of these compounds on TAM-inhibited parental MCF-7 tumors and on TAM-stimulated MCF-7 TAM tumors. Results: We found negligible differences in intratumoral TAM levels between TAM-inhibited parental MCF-7 tumors and TAM-stimulated MCF-7 TAM variants. We did not detect metabolite E (Met E), an estrogenic TAM metabolite, in serum or tumors. Using MCF-7 cells in vitro, we determined that the (Z) isomer of Met E, the form directly produced by TAM metabolism, must be present in the cell at a concentration of over 1000 ng/g to overcome growth inhibition by physiological levels of TAM and antiestrogenic metabolites, but the (E) isomer of Met E was effective at 10 ng/g. We reasoned that conversion of Met E from the (Z) (a weak estrogen) to (E) isomer (a potent estrogen) would be required if formation of Met E were responsible for TAM-stimulated growth. However, fixed-ring TAM, which can only form (Z) Met E, was shown to be as capable as TAM of initiating and maintaining antiestrogen-stimulated growth of MCF-7 tumors in athymic mice. Conclusion: Metabolism and isomerization of TAM to estrogenic compounds is not the mechanism of TAM-stimulated growth in our model. Implication: Other potential mechanisms for TAM-stimulated growth, such as estrogen receptor mutation, must be investigated so that effective strategies can be devised to control breast cancer once therapy fails. [J Natl Cancer Inst 85: 806–812, 1993]
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