||In estrogen receptor positive breast cancer, estrogen stimulates mammary tumor cells to multiply. Tamoxifen, a selective estrogen-receptor modulator, is used to block the binding of estrogen to the estrogen receptor (ER) in breast cancer treatment but therapeutic insensitivity is common. One of the multiple mechanisms responsible for tamoxifen insensitivity could be the loss of estrogen receptor alpha (ER-α). GATA3 and ER-α are involved in a positive cross-regulatory loop, where each one of these factors is required for the transcription of the other gene. In addition, the estrogen receptor positive tumors with good prognosis typically have high GATA3. In the murine T cell lineage, transcriptional activity of GATA3 is negatively regulated by a fetal liver-zinc finger protein 1(Fliz1). However, studies on Fliz1 and GATA3 interaction in breast tumorigenesis are lacking. I hypothesized that Fliz1 would downregulate GATA3 expression and decrease ER-α levels, leading to tamoxifen insensitivity in mouse mammary tumor cells. To test this idea, I used stable transfection to introduce silencing constructs into high Fliz1 expressing mouse mammary tumor cells to study the effect of Fliz1 on GATA3 and ER-α expression. RT-PCR suggests that the knockdown of Fliz1 correlates with increased expression of GATA3 and ER-α expression in murine mammary tumor cells. These findings were further verified with western blotting. Additionally, I have studied the effect of Fliz1 on tamoxifen insensitivity through in vitro cell proliferation assay. I have also utilized an in vivo method to further test my findings. These data partially emphasize the importance of Fliz1 in the down regulation of GATA3 and ER-α and furthers our understanding of the mechanisms that regulate ER-α in breast tumors.