Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.

摘要

BACKGROUND: Long-term tamoxifen treatment of breast cancer can result in tamoxifen-stimulated breast cancer, in which estrogen inhibits tumor growth after tamoxifen withdrawal. We investigated the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human breast cancer. METHODS: Growth of parental estradiol-stimulated MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Protein expression was assessed by western blot analysis. mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. RESULTS: MCF-7E2 tumor growth was stimulated by estradiol (cross-sectional area at week 13 = 1.06 cm2, 95% confidence interval [CI] 0.82 to 1.30 cm2; P<.001) compared with control (0.06 cm2, 95%CI to 0.14 cm2), but tumor growth was inhibited by tamoxifen or fulvestrant. MCF-7TAMLT tumor growth was stimulated by tamoxifen) cross-sectional area at week 10 = 0.60 cm2, 95% CI = 0.50 to 0.70 cm2; P<.001) compared with control (0.02 cm2, 95% CI = 0.00 to 0.04 cm2). For MCF-7TAMLT tumors that were initially 0.35 cm2, estradiol-induced regression to 0.18 cm2 (95% CI 0.15 to 0.21 cm2; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2). Estradiol increased the number of apoptotic cells in tumors by 23% (95% CI = 20% to 26%; P<.001) compared with all other treatments, decreased estrogen receptor alpha(ERalpha) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2eu mRNA and protein and nuclear factor kappaB (NF-kappaB) protein but did not affect Fas ligand protein expression compared with control. Paradoxically, fulvestrant reversed this effect and stimulated MCF-7TAMLT tumor growth apparently through ERalpha-mediated regulation of Fas, HER2eu, and NF-kappaB. CONCLUSION: Physiologic levels of estradiol induced regression of tamoxifen-stimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic/prosurvival factors NF-kappaB and HER2eu.