Raloxifene stimulated endometrial cancer grown in athymic mice: Cross resistance with ICI182,780 and antitumor action of estradiol

Raloxifene (Ral) is used for the prevention of osteoporosis and is being tested for breast cancer prevention. The clinical advantage of Ral over tamoxifen (Tam) is that it appears to produce lower incidence of endometrial cancer (Goldstein SR, Eur J Cancer, 2000 Suppl 4;36:S54-6). However, the STAR (Study of Tamoxifen and Raloxifene) trial is comparing uterine safety with Tam in pastmenopausal women. In advance of the clinical results we developed a new endometrial carcinoma model in the laboratory that is stimulated by Ral (called ECC-1 Ral). Our objective was to assess the effects of estradiol (E2), Tam and the pure antiestrogen ICI182,780 on the growth of this novel human ECC-1 Ral endometrial cancer in athymic mice to verify if there is cross-resistance among the antiestrogens. Methods: We maintained ECC-1 cells in vitro with 1μM Ral for over one year, which resulted in Ral resistant cells. Cells (10 million) were injected in ovariectomized athymic mice (passage 1) and produced Ral-stimulated growth after 14 weeks of treatment (1.5mg daily). Retransplanted tumors (passage 2) produced Ral-stimulated growth after 10 weeks. The third passage was evaluated in response to E2 capsules (0.3cm), Tam (0.5mg/d), Ral (1.5mg/d), ICI182,780 (5mg sc twice weekly) and combinations with E2. All groups contained 10 bitransplanted mice. Results: Tam (0.5mg daily), Ral (1.5mg daily) and ICI182,780 (5mg sc twice weekly) all stimulated the growth of the ECC-1 Ral tumors. In contrast, estrogen did not promote significant tumor growth compared to control group. In addition, E2 was able to inhibit tumor growth in combination with antiestrogens. All tumors were estrogen receptor positive. Conclusion: ECC-1 Ral tumors are cross resistant with Tam, and ICI182,780 but E2 prevents growth. We conclude that ECC-1 Ral tumors in athymic mice are worse than Tam stimulated endometrial tumors (EnCa101 Tam), which are known to respond to ICI182.780.