Abstract A74: Estrogen receptor α-regulated growth and transcription is dependent on X-box binding protein-1 in breast cancer cells

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Abstract This study was designed to investigate the impact of X-Box Binding protein 1 (Xbp1) mRNA knockdown on the estrogen-responsive growth and gene expression in an estrogen receptor α (ERα) positive breast cancer cell line model. Xbp1 is a basic leucine zipper-containing transcription factor that plays a key role in the unfolded protein response (UPR), a cell program that is activated by unfolded or misfolded proteins in the endoplasmic reticulum. MCF7 cells, a model of ERα positive breast cancer, express high levels of Xbp1 and are dependent on estrogen for growth and ERα regulated transcription. Previous studies have revealed that further overexpression of Xbp1 in ERα positive breast cancer cells leads to estrogen independent ERα regulated transcription and anti-estrogen resistance, suggesting that Xbp1 expression influences ERα regulated transcription. Unknown is whether ERα requires Xbp1 as a cofactor for transcription. Here we show that Xbp1 mRNA knockdown by specific siRNAs prevents estrogen responsive growth of MCF7 cells as well as ERα regulated gene expression, while non-specific control siRNAs had little effect. These results, together with the high expression of Xbp1 seen in ERα positive breast cancers, but not in normal mammary ductal cells, suggests that high levels of Xbp1 enable ERα tumor cells to use estrogen as a growth factor. Thus, high levels of Xbp1 expression could represent an early transformation step leading to ERα positive breast cancer, and could explain why normal ERα positive breast ductal cells have not been established as cell lines. Citation Information: Cancer Res 2009;69(23 Suppl):A74.