Breast cancer is the most common cancer among women and is the leading cause of cancer death in women worldwide. Transcription factors forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA3) play important roles in ERα signalling and oestrogen response in breast cancer [1]. FOXA1 modulates how ERα binds to DNA to govern ERα-mediated gene transcription and GATA3 is a marker of differentiation in the luminal epithelium of the breast. Both FOXA1 and GATA3 expression correlate with ERα expression, and both are markers of good prognosis in ER positive, luminal A type breast cancer that responds favourably to endocrine therapy [2]. However, it remains unclear how ESR1, FOXA1 and GATA3 together, contribute to the development of breast cancer.
We identified FOXA1- and GATA3-associated gene expression patterns by knocking down FOXA1 and GATA3 mRNA independently using siRNA, in ER positive MCF7 breast cancer cells, and capturing the transcriptomic changes using microarrays. FOXA1-dependent genes were significantly enriched for molecular pathways known to be associated with NFKB and E2F, whilst GATA3-dependent genes were significantly enriched for molecular pathways associated with NFKB and TGFB. Genes that were differentially regulated after FOXA1 and GATA3 knockdown were also highly enriched for E2F transcription factor binding sites. Although knockdown of both FOXA1 and GATA3 resulted in changes in ERα mRNA expression, GATA3 mRNA expression remained unchanged after FOXA1 knockdown and FOXA1 mRNA expression remained unchanged after GATA3 knockdown, suggesting they might operate independently on ERα. Bioinformatics analyses of breast cancer microarray data from 1034 patients also support the current dogma that both FOXA1 and GATA3 are master regulators of ERα signalling.
The regulatory relationship between FOXA1, GATA3 and ERα in breast cancer appears to be complex and more work is needed to define the individual and contributory roles that these genes play in breast cancer and ERα signalling.