A set of accessible enhancers enables the initial response of breast cancer cells to physiological progestin concentrations.
Roser ZaurinRoberto FerrariAna Silvina NachtJose CarbonellFrançois Le DilyJofre Font-MateuLara Isabel de Llobet CucalonEnrique VidalAntonios LioutasMiguel BeatoGuillermo P VicentPublished in: Nucleic acids research (2021)
Here, we report that in T47D breast cancer cells 50 pM progestin is sufficient to activate cell cycle entry and the progesterone gene expression program. At this concentration, equivalent to the progesterone blood levels found around the menopause, progesterone receptor (PR) binds only to 2800 genomic sites, which are accessible to ATAC cleavage prior to hormone exposure. These highly accessible sites (HAs) are surrounded by well-organized nucleosomes and exhibit breast enhancer features, including estrogen receptor alpha (ERα), higher FOXA1 and BRD4 (bromodomain containing 4) occupancy. Although HAs are enriched in RAD21 and CTCF, PR binding is the driving force for the most robust interactions with hormone-regulated genes. HAs show higher frequency of 3D contacts among themselves than with other PR binding sites, indicating colocalization in similar compartments. Gene regulation via HAs is independent of classical coregulators and ATP-activated remodelers, relying mainly on MAP kinase activation that enables PR nuclear engagement. HAs are also preferentially occupied by PR and ERα in breast cancer xenografts derived from MCF-7 cells as well as from patients, indicating their potential usefulness as targets for therapeutic intervention.
Keyphrases
- estrogen receptor
- breast cancer cells
- cell cycle
- gene expression
- end stage renal disease
- cell proliferation
- randomized controlled trial
- transcription factor
- induced apoptosis
- dna methylation
- binding protein
- chronic kidney disease
- particulate matter
- dna binding
- prognostic factors
- cell cycle arrest
- dna damage
- air pollution
- social media
- single molecule
- genome wide
- oxidative stress
- dna repair
- patient reported outcomes
- heavy metals
- tyrosine kinase
- endoplasmic reticulum
- high density
- risk assessment
- cell death
- young adults
- pi k akt