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Antitumor Action of Physiological Estradiol on Tamoxifen-stimulated Breast Tumors Grown in Athymic Mice¹

Department of Surgery [K. Y., D. J. B., G. E.], R. H. Lurie Comprehensive Cancer Center [E-S. L., J. I. M. S., V. C. J.], and the Division of Medical Oncology [R. M. O.], Northwestern University Medical School, Chicago, Illinois 60611

The estrogen receptor (ER)-positive MCF-7 breast cancer cell line can be transplanted into athymic mice and grown into tumors with estradiol (E₂) support. Tamoxifen (TAM) blocks E₂-stimulated tumor growth; however, continuous TAM treatment results in transplantable tumors within a year that will grow with either E₂ or TAM (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183–5187, 1988). Although this model may represent the development of TAM resistance for the treatment of advanced breast cancer, no laboratory model exists to study the exposure of breast cancer to 5 years of adjuvant TAM therapy. We have addressed this issue and report the development and characterization of two tumor lines, MCF-7TAM and MT2, which have been serially transplanted into TAM-treated athymic mice for >5 years. The MCF-7TAM tumor rapidly regresses in response to E₂ and then about 50% of tumors regrow in response to E₂. Interestingly, tumor regression does not occur if TAM treatment is stopped, probably because E₂ levels are too low in ovariectomized athymic mice. The development of the antitumor effect of E₂ was documented for MT2 tumors over a 1-year period; TAM-stimulated tumor growth was retained, but E₂ caused progressively less of a stimulatory effect. Most importantly, E₂-stimulated tumors that regrew after initial tumor regression in both MCF-7TAM and MT2 lines were again responsive to TAM to block E₂-stimulated growth. Unlike MCF-7 tumors, the MT2 tumor line contains a single point mutation, Asp351Tyr, in the ER, which was retained after the development of E₂-stimulated regrowth. The mutation is associated with increased estrogen-like actions for the TAM-ER complex (A. S. Levenson et al., Br. J. Cancer, 77: 1812–1819, 1998), but we conclude that the mutant ER is not required for TAM resistance. On the basis of the new breast cancer models presented, we propose a cyclic sensitivity to TAM that may have important clinical implications: (a) it is possible that a woman’s own estrogen may produce an antitumor effect on the presensitized micrometastatic disease after 5 years of TAM. Long-term antitumor action occurs because the drug is stopped, but resistance accumulates and tumors start to grow if adjuvant therapy is continued; and (b) although in the clinic TAM-resistant tumors respond to second-line therapies that cause estrogen withdrawal, e.g., pure antiestrogens or aromatase inhibitors, estrogen therapy may also be effective and return the tumor to TAM responsiveness. In this way, a hormone-responsive tumor may be controlled longer in the patient with advanced disease.

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