4-Hydroxytamoxifen differentially exerts estrogenic and antiestrogenic effects on discrete subpopulations of human breast cancer cells.
Functional heterogeneity within populations of breast cancer cells contribute to the seemingly paradoxical effects of antiestrogens and the development of antiestrogen "resistance." Our objectives were to determine the degree to which T-47D cells may respond inappropriately (positively) to the antiestrogen 4-hydroxytamoxifen (HOT) alone, and whether all cells that respond to the stimulatory effects of estradiol-17beta (E2) are inhibited by the addition of HOT. Single, living T-47D cells were transfected by microinjection with an estrogen response element (ERE)-driven luciferase reporter plasmid. Transfected cells were then treated with medium alone, HOT, E2 or a combination thereof on consecutive days, exposed to the substrate luciferin and subjected to quantification of photonic emissions reflective of ERE-stimulated activity. This analysis revealed a subpopulation of cells that exhibited increased ERE-driven photonic activity in response to HOT. In companion studies, E2-stimulated ERE activity was reversed (on average) with HOT addition. However, analysis of individual cells revealed that although HOT reduced photonic activity in the majority (89.2%) of E2-responsive cells, there was a small subset (10.8% of the population) that was stimulated by E2 + HOT cotreatment. Our data support the hypothesis that these cells possess an intrinsic "resistance" to antiestrogenic agents, and that this could contribute to the remodeling of tumor cell populations toward a "resistant" phenotype.
Willard
S T
ST
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston 29425-2204, USA.
Abrahman
E J
EJ
Faught
W J
WJ
Leaumont
D C
DC
Frawley
L S
LS
D001943:Breast Neoplasms; D004351:Drug Resistance; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D049454:Firefly Luciferin / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D017785:Photons; D020218:Response Elements / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D004967:Estrogens; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D049454:Firefly Luciferin; D008156:Luciferases