IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Background: IQGAP1 is a scaffold protein that modulates diverse signaling pathways. Results: IQGAP1 binds to estrogen receptor- (ER) and ER, and knockdown of IQGAP1 impairs 17-estradiol (E-2)-stimulated transcriptional activation in human breast epithelial cells. Conclusion: IQGAP1 modulates ER function and is required for maximal E-2 function. Significance: IQGAP1 might be a therapeutic target for patients with breast carcinoma. The estrogen receptor (ER) is a steroid hormone receptor that acts as a transcription factor, modulating genes that regulate a vast range of cellular functions. IQGAP1 interacts with several signaling proteins, cytoskeletal components, and transmembrane receptors, thereby serving as a scaffold to integrate signaling pathways. Both ER and IQGAP1 contribute to breast cancer. In this study, we report that IQGAP1 binds ER and ER. In vitro analysis with pure proteins revealed a direct interaction between IQGAP1 and ER. Investigation with multiple short fragments of each protein showed that ER binds to the IQ domain of IQGAP1, whereas the hinge region of ER is responsible for binding IQGAP1. In addition, IQGAP1 and ER co-immunoprecipitated from cells, and the association was modulated by estradiol. The interaction has functional effects. Knockdown of endogenous IQGAP1 attenuated the ability of estradiol to induce transcription of the estrogen-responsive genes pS2, progesterone receptor, and cyclin D1. These data reveal that IQGAP1 binds to ER and modulates its transcriptional function, suggesting that IQGAP1 might be a target for therapy in patients with breast carcinoma.