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JNCI Journal of the National Cancer Institute 2003 95(21):1597-1608; doi:10.1093/jnci/djg079
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© 2003 Oxford University Press

ARTICLE

Paradoxical Action of Fulvestrant in Estradiol-Induced Regression of Tamoxifen-Stimulated Breast Cancer

Clodia Osipo, Csaba Gajdos, Hong Liu, Bin Chen, V. Craig Jordan

Affiliations of authors: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL (CO, HL, BC, VCJ); Department of Surgery, University of Alabama, Birmingham (CG).

Correspondence to: V. Craig Jordan, OBE, PhD, DSc, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 8258 Olson, 303 E. Chicago Ave., Chicago, IL 60611 (e-mail: vcjordan{at}northwestern.edu).

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 = -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 {alpha}(ER{alpha}) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor {kappa}B (NF-{kappa}B) 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 ER{alpha}-mediated regulation of Fas, HER2/neu, and NF-{kappa}B. 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-{kappa}B and HER2/neu.


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Correspondence about this Article

Re: Playing the Old Piano: Another Tune for Endocrine Therapy
Dieter Koeberle, Lucien Perey, and Beat Thuerlimann
J Natl Cancer Inst 2004 96: 555-556. [Extract] [Full Text] [PDF]

RESPONSE: Re: Playing the Old Piano: Another Tune for Endocrine Therapy
V. Craig Jordan, Clodia Osipo, Dong Cheng, and Joan S. Lewis
J Natl Cancer Inst 2004 96: 556-557. [Extract] [Full Text] [PDF]

RESPONSE: Re: Playing the Old Piano: Another Tune for Endocrine Therapy
Daniel F. Hayes
J Natl Cancer Inst 2004 96: 557. [Extract] [Full Text] [PDF]

Editorial about this Article

Playing the Old Piano: Another Tune for Endocrine Therapy?
Daniel F. Hayes
J Natl Cancer Inst 2003 95: 1565-1567. [Extract] [Full Text] [PDF]

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Apoptotic Action of 17{beta}-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo
Hong Liu, Eun-Sook Lee, Csaba Gajdos, Sandra Timm Pearce, Bin Chen, Clodia Osipo, Jessica Loweth, Kevin McKian, Alexander De Los Reyes, Laura Wing, and V. Craig Jordan
J Natl Cancer Inst 2003 95: 1586-1597. [Abstract] [Full Text] [PDF]



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