Positive Cross-Regulatory Loop Ties GATA-3 to Estrogen Receptor α Expression in Breast Cancer

Abstract

The transcription factor GATA-3 is required for normal mammary gland development, and its expression is highly correlated with estrogen receptor alpha (ER alpha) in human breast tumors. However, the functional role of GATA-3 in ER alpha-positive breast cancers is yet to be established. Here, we show that GATA-3 is required for estradiol stimulation of cell cycle progression in breast cancer cells. The role of GATA-3 in estradiol signaling requires the direct positive regulation of the expression of the ER alpha gene itself by GATA-3. GATA-3 binds to two cis-regulatory elements located within the ER alpha gene, and this is required for RNA polymerase II recruitment to ER alpha promoters. Reciprocally, ER alpha directly stimulates the transcription of the GATA-3 gene, indicating that these two factors are involved in a positive cross-regulatory loop. Moreover, GATA-3 and ER alpha regulate their own expression in breast cancer cells. Hence, this transcriptional coregulatory mechanism accounts for the robust coexpression of GATA-3 and ER alpha in human breast cancers. In addition, these results highlight the crucial role of GATA-3 for the response of ER alpha-positive breast cancers to estradiol. Moreover, they identify GATA-3 as a critical component of the master cell-type-specific transcriptional network including ER alpha and FoxA1 that dictates the phenotype of hormone-dependent breast cancer.