There have been several reports of women who have tumor relapse while on tamoxifen therapy, followed by tumor regression after tamoxifen withdrawal. In such apparently tamoxifen-stimulated tumors, there is likely a genetic change which increases the estrogenicity of tamoxifen. In this study, we determine if increasing the number of estrogen response elements (EREs) in the promoter region of a reporter gene can alter the agonistic activity of fixed-ring 4-hydroxytamoxifen. We show that increasing the number of EREs in the promotor region increases the transcriptional response of the reporter plasmid to estradiol. We also find that while fixed-ring 4-hydroxytamoxifen is unable to stimulate transcription when one ERE is present, transcriptional activation can occur with multiple EREs. These results demonstrate that ERE amplification could explain the agonistic properties of tamoxifen, and suggests a novel mechanism to explain tamoxifen-stimulated breast cancer growth.