Rabbit Anti-Human ESR1 (Phospho-Tyr537) polyclonal antibody

Background Estrogen receptor alpha (ESR1) plays a critical role in promoting growth of various cancers. Yet, its role in the development of pancreatic cancer is not well-defined. A less studied region of ESR1 is the hinge region, connecting the ligand binding and DNA domains. rs142712646 is a rare SNP in ESR1, which leads to a substitution of arginine to cysteine at amino acid 269 (R269C). The mutation is positioned in the hinge region of ESR1, hence may affect the receptor structure and function. We aimed to characterize the activity of R269C-ESR1 and study its role in the development of pancreatic cancer. Methods Transcriptional activity was evaluated by E2-response element (ERE) and AP1 -luciferase reporter assays and qRT-PCR. Proliferation and migration were assessed using MTT and wound healing assays. Gene-expression analysis was performed using RNAseq. Results We examined the presence of this SNP in various malignancies, using the entire database of FoundationOne and noted enrichment of it in a subset of pancreatic non-ductal adenocarcinoma (n = 2800) compared to pancreatic ductal adenocarcinoma (PDAC) as well as other tumor types (0.53% vs 0.29%, p = 0.02). Studies in breast and pancreatic cancer cells indicated cell type-dependent activity of ESR1 harboring R269C. Thus, expression of R269C-ESR1 enhanced proliferation and migration of PANC-1 and COLO-357 pancreatic cancer cells but not of MCF-7 breast cancer cells. Moreover, R269C-ESR1 enhanced E2-response elements (ERE) and AP1-dependent transcriptional activity and increased mRNA levels of ERE and AP1-regulated genes in pancreatic cancer cell lines, but had a modest effect on MCF-7 breast cancer cells. Accordingly, whole transcriptome analysis indicated alterations of genes associated with tumorigenicity in pancreatic cancer cells and upregulation of genes associated with cell metabolism and hormone biosynthesis in breast cancer cells. Conclusions Our study shed new light on the role of the hinge region in regulating transcriptional activity of the ER and indicates cell-type specific activity, namely increased activity in pancreatic cancer cells but reduced activity in breast cancer cells. While rare, the presence of rs142712646 may serve as a novel genetic risk factor, and a possible target for therapy in a subset of non-ductal pancreatic cancers.

The impact of progestins (i.e. synthetic forms of progesterone) on aquatic organisms has drawn increasing attention due to their widespread occurrence in the aquatic environments and potential effects on the endocrine system of fish. In this study, the effects of norethindrone (NET, a progestin) on the reproductive behavior, sex hormone production and transcriptional expressions were evaluated by exposing female zebrafish to NET at 0, 3.1, 36.2 and 398.6 ng L-1 for 60 days. Results showed that NET impaired the mating behaviors of female at 36.2 and 398.6 ng L-1 exhibited by males and increased the frequency of atretic follicular cells in the ovary exposed to NET at 398.6 ng L-1. As for sex hormones, plasma testosterone concentration in zebrafish increased, while estradiol concentration decreased. Up-regulation of genes (Npr, Mpra, Mpr beta, Fsh beta, L beta, Tshb, Nis and Dio2) was detected in the brain of fish exposed to NET at 398.6 ng L-1. The transcriptional levels of genes (Esr1, Vtg1, Ar, Cyp19a, Cyp11b and Ptgs2) were generally inhibited in the ovary of zebrafish by NET at 398.6 ng L-1. Moreover, the transcripts of genes (Vtg1, Esr1, Ar and Pgr) in the liver were reduced by NET at 36.2 and 398.6 ng L-1. Our findings suggest that NET can potentially diminish the of fish populations not only by damaging their reproductive organs, but also by altering their mating behavior through the changes in the expressions of genes responsible for the production of sex hormones.