Antiprogestins prevent progesterone receptor binding to hormone responsive elements in vivo

Area of Science:

• Molecular Endocrinology
• Pharmacology
• Cancer Biology

Background:

• Antiprogestins are pharmaceuticals that inhibit progesterone action by competing for progesterone receptor binding.
• The mechanism by which antiprogestins render the progesterone receptor complex functionally inactive remains unclear.
• Previous models relied on indirect evidence due to challenges in visualizing in vivo receptor-DNA interactions.

Purpose of the Study:

• To investigate the in vivo mechanism of antiprogestin action on progesterone receptor binding to DNA.
• To elucidate why antiprogestin-progesterone receptor complexes are functionally inactive.

Main Methods:

• Genomic footprinting analysis was employed to study ligand-dependent binding of endogenous progesterone receptor.
• Experiments were conducted on a chromosomally integrated mouse mammary tumor virus long terminal repeat in a human mammary carcinoma cell line.
• The effects of antiprogestins RU 486 and ZK 98299 on receptor binding and agonist-induced footprints were assessed.

Main Results:

• Ligand-dependent binding of endogenous progesterone receptor to hormone-responsive elements (HREs) was demonstrated in vivo.
• Antiprogestins RU 486 and ZK 98299 did not promote progesterone receptor binding to the natural HRE in vivo.
• Antiprogestins induced a rapid disappearance of the agonist-induced progesterone receptor footprint, even at inhibitory concentrations.

Conclusions:

• Antiprogestins interfere with progesterone receptor function by preventing its specific binding to DNA.
• This mechanism explains the functional inactivity of antiprogestin-bound progesterone receptor complexes.
• Findings provide direct in vivo evidence for antiprogestin action at the DNA-binding level.