Regulation of fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen.
During neoplastic growth and metastasis, the immune system responds to the tumor by developing both cellular and humoral immune responses. In spite of this active response, tumor cells escape immune surveillance. We previously showed that FasL expression by breast tumor plays a central role in the induction of apoptosis of infiltrating Fas-immune cells providing the mechanism for tumor immune privilege. In the present study, we showed that FasL in breast tissue is functionally active, and estrogen and tamoxifen regulate its expression. We identified an estrogen recognizing element like-motif in the promoter region of the FasL gene, suggesting direct estrogen effects on FasL expression. This was confirmed by an increase in FasL expression in both RNA and protein levels in hormone sensitive breast cancer cells treated with estradiol. This effect is receptor mediated since tamoxifen blocked the estrogenic effect. Interestingly, tamoxifen also inhibited FasL expression in estrogen-depleted conditions. Moreover, an increase in FasL in breast cancer cells induces apoptosis in Fas bearing T cells and, tamoxifen blocks the induction of apoptosis. These studies provide evidence that tamoxifen inhibits FasL expression, allowing the killing of cancer cells by activated lymphocytes. This partially explains the protective effect of tamoxifen against breast cancer.
Mor
G
G
Department of Obstetrics and Gynecology, Yale University Medical School, 333 Cedar St. FMB 202, New Haven, CT 06520, USA. gil.mor@yale.edu
Kohen
F
F
Garcia-Velasco
J
J
Nilsen
J
J
Brown
W
W
Song
J
J
Naftolin
F
F
D001943:Breast Neoplasms / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology*; D053222:Fas Ligand Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D013629:Tamoxifen; D004958:Estradiol