FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

Abstract

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.

Chromatin regulates genome-wide transcription factor binding affinities

“…Interestingly, high affinity FOXA1 sites were remarkably less accessible compared to low affinity sites ( Extended Data Fig. 3a ), which is in agreement with the ability of this transcription factor to bind and subsequently open compacted chromatin, rendering it accessible to other transcription factors 25,26 . The fact that binding affinities of FOXA1 showed a strong correlation with H3K4me1 ( Extended Data Fig.…”

“…2b, Extended Data Fig. 3a ), possibly reflecting its ability to open condensed chromatin 26 . Here, FOXA1 was able to bind both promoters and enhancers with reduced accessibility, in particular at high affinity binding sites ( Extended Data Fig.…”

The POLR3G Subunit of Human RNA Polymerase III Regulates Tumorigenesis and Metastasis in Triple-Negative Breast Cancer

“…Deletion of POLR3G activated the expression of luminal fate-specific proteins FOXA1 and androgen receptor (AR). FOXA1 is not only required for developmental specification, but also for postnatal differentiation of breast epithelial cells into luminal cell types [ 45 , 46 ]. We also noticed that the expression of GATA3 was negatively correlated to the expression of POLR3G in clinical data ( Table S2 ).…”

An Integrated Study on the Differential Expression of the FOX Gene Family in Cancer and Their Response to Chemotherapy Drugs

“…FOXA1 , an androgen receptor (AR) chromatin-binding precursor in the prostate epithelium, was reprogrammed to neuroendocrine-specific regulatory elements [ 55 ]. In addition, a previous study revealed that FOXA1 , which established estrogen-responsive transcriptomes, was a pioneer of nuclear receptor action in breast cancer [ 56 ]. The interaction of FOXA1 with co-factors such as ESR1 and E2F1 enhanced the susceptibility of breast cancer [ 57 ].…”