Rapid development of tamoxifen-stimulated mutant p53 breast tumors (T47D) in athymic mice

MCF-7 cells are used routinely to study tamoxifen-stimulated drug resistanc e in vivo. However, unlike MCF-7 cells, T47D cells express mutant p53 prote in and lose the estrogen receptor (ER) during long-term estrogen deprivatio n in vitro [Pink et al,, Br, J, Cancer, 74: 1227-1236, 1996 (erratum, Br. J . Cancer, 75: 1557, 1997)], As a result, T47D tumors may respond differentl y from MCF-7 tumors to long-term tamoxifen treatment. Ovariectomized athymi c mice were given injections bilaterally with T47D cells (5 x 10(5)) into t he mammary fat pads. A rapidly growing estradiol responsive tumor (T47D:E2) was established and 0.5 mg of tamoxifen given daily blocked estrogen-stimu latcd growth. In subsequent experiments, low doses of tamoxifen (0.17 mg or 0.5 mg) did not produce tamoxifen-stimulated tumors at 14 weeks, whereas h igh-dose tamoxifen (1.5 mg) consistently produced tamoxifen-stimulated tumo rs (T47D:Tam; 17 tumors/20 sites) at 8 weeks. In contrast, 1.5 mg of tamoxi fen produced tamoxifen-stimulated MCF-7 tulfiors (MCF-7: Tam2) at a slower rate (20 weeks) and less consistently (4 tumors/2S sites). When the T47D:Ta m tumor was passaged, it grew maximally with either 1.5 mg of tamoxifen or a 1-cm estradiol (premenopausal levels) capsule, and similar results were o btained with MCF-7:Tam2 tumors. interestingly; when T47D:Tam tumors were tr eated with the 0.5 mg of tamoxifen, tumors grew only to 50% maximum, All of the tumors originating from MCF-7 and T47D cells expressed ER at similar l evels; therefore, tamoxifen did not select for an ER-negative tumor. In con clusion, we have shown that tamoxifen-stimulated T47D p53 mutant tumors can be developed rapidly with high-dose therapy (1.5 mg daily). The results fr om this model provide new opportunities to investigate the rapid developmen t of drug resistance to adjuvant tamoxifen in patients with mutant p53 brea st tumors.