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 A (ERA) in human breast tumors. However, the functional role of GATA-3 in ERApositive 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 ERa gene itself by GATA-3. GATA-3 binds to two cis-regulatory elements located within the ERa gene, and this is required for RNA polymerase II recruitment to ERa promoters. Reciprocally, ERA 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 ERA regulate their own expression in breast cancer cells. Hence, this transcriptional coregulatory mechanism accounts for the robust coexpression of GATA-3 and ERA in human breast cancers. In addition, these results highlight the crucial role of GATA-3 for the response of ERA-positive breast cancers to estradiol. Moreover, they identify GATA-3 as a critical component of the master cell-type-specific transcriptional network including ERA and FoxA1 that dictates the phenotype of hormone-dependent breast cancer. [Cancer Res 2007;67(13):6477-83]

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

“…Thus, the identities of genes differentially expressed during MCF7-LTED adaptation may support the important role of the non-genomic function of ERa. GATA3, which encodes for a key transcription factor for luminal differentiation tightly coregulated with and by ERa in breast cancer cells (Eeckhoute et al, 2007;Kouros-Mehr et al, 2008), showed significant underexpression during MCF7-LTED adaptation (Figure 3b). In contrast, RAF1, which encodes for a key factor in mitogen-activated protein kinase signaling and the associated resistance to tamoxifen treatment (Iorns et al, 2008), showed significant overexpression ( Figure 3b).…”

The significance of GATA3 expression in breast cancer: a 10-year follow-up study

“…GATA3 and ER are involved in a positive cross-regulatory loop, where each one of these factors is required for the transcription of the other gene. Furthermore, GATA3 and ER autoregulate their own expression and one would expect that GATA3 expression would be informative of the functional status of the ER pathway [10]. In welldifferentiated, low-grade carcinomas such as luminal A breast cancers both ER and GATA3 are expected to show strong expression.…”

“…Furthermore, GATA3 and ER autoregulate their own expression. These mechanisms could explain the high correlation of GATA3 and ER expression in luminal A breast tumors [10]. Therefore, by regulation of ER expression, GATA3 is crucial for estradiol-stimulated progression of ER-positive breast cancer.…”

“…Moreover, GATA3 is linked to two other gene regulatory factors, namely FoxA1 and estrogen receptor alpha [10]. GATA3 is normally expressed at high levels, in association with ER, in the luminal epithelial cells.…”

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

“…GATA-3 is a critical component of the master cell-type-specific transcriptional network, as well as key determinant of mammary gland morphogenesis and luminal cell specification [25,37]. Expression of GATA-3, ERa, and PR is also highly correlated in mammary development and cancer [38]. These data provide evidence of activation of both androgen-and estrogen-regulated pathways in heterotypic prostate--mammary tissue recombinants that were grown in male hosts and thus exposed to androgen stimulation.…”