ABSTRACT
BACKGROUND: The human progesterone receptor (hPR) belongs to the steroid receptor family. It may be found as monomers (A and B) and or as a dimer (AB). hPR is regarded as the prognostic biomarker for breast cancer. In a cellular dimer system, AB is the dominant species in most cases. However, when a cell coexpresses all three isoforms of hPR, the complexity of the action of this receptor increases. For example, hPR A suppresses the activity of hPR B, and the ratio of hPR A to hPR B may determine the physiology of a breast tumor. Also, persistent exposure of hPRs to nonendogenous ligands is a common risk factor for breast cancer. Hence we aimed to study progesterone and some nonendogenous ligand interactions with hPRs and their molecular docking. METHODS AND RESULTS: A pool of steroid derivatives, namely, progesterone, cholesterol, testosterone, testolectone, estradiol, estrone, norethindrone, exemestane, and norgestrel, was used for this in silico study. Dockings were performed on AutoDock 4.2. We found that estrogens, including estradiol and estrone, had a higher affinity for hPR A and B monomers in comparison with the dimer, hPR AB, and that of the endogenous progesterone ligand. hPR A had a higher affinity to all the docked ligands than hPR B. CONCLUSION: This study suggests that the exposure of estrogens to hPR A as well as hPR B, and more particularly to hPR A alone, is a risk factor for breast cancer.
ABSTRACT
With increasing use of plant-based cancer chemotherapeutic agents, exploring the antiproliferative effects of phytochemicals has gained increasing momentum for anticancer drug design. The present study was undertaken to investigate the effect of root bark of Juglans regia (RBJR) organic extracts on cell proliferation, and to determine the molecular mechanism of RBJR-induced cell death by determining the expression of Bcl-2, Bax, caspases, Tp53, Mdm-2 and TNF-alpha in MDA-MB-231 human breast cancer cells. The results demonstrate that WNRB suppressed proliferation and induced apoptosis in a dose and time dependent manner by modulating expression of key genes. This involved characteristic changes in cytoplasmic and nuclear morphology, DNA fragmentation (TUNEL assay), levels of mRNA and expression of corresponding proteins. Real Time PCR and western blot analysis revealed that the expression of of Bax, caspases, tp53, and TNF-alpha was markedly increased in MBA-MB-231 cells treated with the RBJR extract. In contrast Bcl2 and mdm-2 expression was down regulated after exposure. In summary, our data suggest the presence of bioactive compound(s) in WNRB capable of killing breast carcinoma cells through induction of apoptosis, and therefore a candidate source of anticancer drugs.
