Effects of ICI 182,780 on tamoxifen-stimulated breast and endometrial cancer

Drug resistance to tamoxifen (TAM) in the form of stimulated growth limits long-term treatment. Evidence suggests an increase in AP-1 mediated pathways stimulated by TAM to cause tumor growth. Studies in vitro show that ICI can also enhance AP-1 through the estrogen receptor (ER). (Paech K, Science 1997;277:1508-10) Thus, ICI may be limited as a second line agent after T AM. We have addressed this concern by evaluating the effectiveness of ICI to control models of TAM-stimulated tumor growth in vivo. Methods: The effects of ICI (5mg Id/week alone, 5mg and 10mg ICI/week+0.3cm E2 capsule) were examined on three TAM-resistant breast cancer (BC) models and one TAM-resistant endometrial cancer (EC) model. All groups contained 10 bitransplanted ovariectomized athymic nude mice. Results: Higher doses (10 mg/week) of ICI effectively blocked estradiol-stimulated tumor growth in all BC and EC models. Unlike TAM. ICI did not stimulate tumor growth when administered alone. All tumors were ER positive but ICI produced a dose-related decrease in ER levels in each tumor model determined by using western blot. Conclusion: Since ICI did not stimulate the growth of any TAM-resistant breast or endometrial tumor model, we found no evidence to support the view that activation of AP-1 by the ICI:ER complex could stimulate tumor growth. We suggest that since ICI destroys ER in the tumor this then interrupts the signal transduction pathway and prevents growth. The studies of ICI showing the activation of AP-1 in vitro are an artifact that does not translate to therapeutic cross-resistance. Supported by SPORE CA89018-01 and the Avon Products Foundation.