THE IMPORTANCE OF TAMOXIFEN METABOLISM IN TAMOXIFEN-STIMULATED BREAST-TUMOR GROWTH

The acquired ability of tamoxifen to stimulate tumor growth has been s uggested as one mechanism for the development of treatment failure in breast cancer. We have reported that tamoxifen-stimulated MCF-7 breast tumors in nude mice display reduced tamoxifen levels as compared with tamoxifen-inhibited tumors and an altered metabolite profile with iso merization of trans-4-hydroxytamoxifen to a weak antiestrogen and the production of metabolite E, an estrogenic metabolite. To investigate f urther the importance of tamoxifen metabolism in this model, we quanti fied levels of tamoxifen and major metabolites in tamoxifen-stimulated as compared with tamoxifen-inhibited MCF-7 tumors growing in nude mic e and employed tamoxifen analogs resistant to metabolism. Tamoxifen-st imulated tumors have a relative abundance of cis-4-hydroxytamoxifen an d metabolite E. However, in vivo treatment of mice carrying tamoxifen- stimulated tumors with fixed-ring nonisomerizable tamoxifen analogs or with nafoxidine, a nonsteroidal antiestrogen with a different structu re, nonetheless resulted in tumor growth stimulation. Tumors were also stimulated by a deoxytamoxifen analog resistant to conversion to meta bolite E. Growth of tamoxifen-stimulated tumors was inhibited by a pur e steroidal antiestrogen, ICI 182,780, suggesting the need for clinica l trials of this drug in patients with tamoxifen resistance. Growth of tamoxifen-stimulated tumors was further stimulated by estrogen replen ishment, and this estrogen stimulation could be blocked by tamoxifen i ndicating that tamoxifen has both agonist and antagonist properties in these tumors. This study suggests that tamoxifen-stimulated tumor gro wth in this model is not due to isomerization or metabolism of tamoxif en to less antiestrogenic or more estrogenic metabolites. The mechanis ms by which tamoxifen acquires more potent in vivo agonist properties, resulting in tumor growth stimulation over time, remain to be defined .