The human progesterone receptor (hPR), like other members of the steroid receptor family of proteins, is a ligand-induced transcription factor which mediates the effects of progesterone.1
Progesterone is well known for its critical role in regulation of the normal physiology of the ovary, uterus, mammary gland, as well as brain development during childhood. Progesterone also plays an important role in the maintenance of the cardiovascular, central nervous, and skeletal systems.4
The importance of the hPR can therefore be understood from its extensive involvement in human physiological processes.
hPR is comprised of specific functional domains, including the central DNA-binding domain and a carboxyl-terminal ligand-binding domain. The central DNA-binding and ligand-binding domains are the sites of hPR activity. In addition to these domains, hPR have many elements with activator and inhibitory functions enhancing and repressing the transcriptional activation of hPR by their interaction with different transcriptional coregulators.3,8–12 Cytoplasmic hPR have been found as multiprotein chaperone complexes which facilitate their inactive conformation, whereby a ligand can bind with hPR.13
Two distinct isoforms (hPR A and hPR B) of hPR have been reported previously, and differ by an additional amino acid at position 164 in hPR B. These differences arise as a result of either alternate initiation of translation by the same mRNA or by transcription from alternate promoters within the same gene.15
Our understanding of the mechanisms underlying the different activities of these two isoforms of human hPR is limited. However, structural and functional studies indicate that the hPR B isoform contains an additional domain, AF3, that accounts for the transcriptional activity of hPR B by suppressing the activity of an inhibitory domain contained within the sequences common to hPR A and hPR B.11
The evidence suggests that the two isoforms acquire different conformations within the cell, and hence interact with distinct coregulators, ie, the coregulators of hPR A are different from those of hPR B.18
Much of our knowledge regarding the structure and function of hPR A and hPR B comes from models of single hPR isoform expression and models where the hPR homodimer is the dominant molecular species. However, cell types which coexpress the hPR isoforms may possibly have all three kinds of molecules, ie, hPR A, hPR B, and hPR AB, which increases the complexity of the action of hPR.
hPR is a ligand-activated receptor, and its activation/deactivation is associated with the pathogenesis of many diseases, including breast cancer.21
Hence, the specificity of hPR with regard to interaction with its ligand (progesterone) is an important area of research. It has been reported that prolonged exposure to certain nonendogenous ligands, particularly estrogens (which are steroid derivatives) is the strongest risk factor for breast cancer.23
In the absence of progesterone, the hPR A:hPR B ratio influences the biology of estrogen receptor-positive tumors and their response to treatment, and hPR A isoforms are functionally dominant in progesterone-deficient states. This explains why PR A-rich tumors are particularly aggressive.25
We hypothesized that hPR A, hPR B, and hPR AB have different affinities for different ligands, based on conditions such as the availability of progesterone and the concentration of hPR monomers and dimers, which may be a possible cause for the development of breast cancer. The aim of our study was to test this hypothesis and find the affinities of the different steroid derivatives for hPRs. Hence, other steroids that can trigger the development of breast cancer by forming a ligand receptor complex with hPR can be predicted. A battery of steroid derivatives, namely, progesterone (DB00396), cholesterol (DB04540), testosterone (DB00624), testolectone (DB00894), estradiol (DB00783), estrone (DB00655), norethindrone (DB00717), exemestane (DB00990), and norgestrel (DB00506), was used for this in silico study ().
Structure of ligands (as retrieved from Drug Bank) used for docking study.