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- Title
Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.
- Authors
Osipo, Clodia; Gajdos, Csaba; Hong Liu; Bin Chen; Jordan, V. Craig; Liu, Hong; Chen, Bin
- Abstract
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 MCF7E[sub 2] 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-7E[sub 2] 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 = -0.02 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 α(ERα) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor κB (NF-κB) 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 ERα-mediated regulation of Fas, HER2/neu, and NF-κB. Conclusion: Physiologic levels of estradiol induced regression of tamoxifenstimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic/ prosurvival factors NF-κB and HER2/neu.
- Subjects
BREAST cancer treatment; ESTRADIOL; TAMOXIFEN; ONCOLOGY
- Publication
JNCI: Journal of the National Cancer Institute, 2003, Vol 95, Issue 21, p1597
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djg079