Brca1 deficiency exacerbates estrogen-induced dna damage and genomic instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptora- negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability.We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell type

Anti-invasive and anti-proliferative effects of shRNA-loaded poly(lactide-co-glycolide) nanoparticles following RAN silencing in MDA-MB231 breast cancer cells

Background Overexpression of the RAN GTP (RAN)gene has been shown to be linked to metastatic activity of MDAMB231 human breast cancer cells by increasing Ras/MEK/ ERK and PI3K/Akt/mTORC1 signalling. The aim of this study was to investigate the potential of polymeric nanoparticles to deliver two novel shRNA sequences, targeted against the RAN gene, to MDA-MB231 cells grown in culture and to assess their effects in a range of biological assays. Methods Biodegradable PLGA nanoparticles, loaded with shRNA-1 and shRNA-4, were fabricated using a double emulsion solvent evaporation technique and characterised for size, zeta potential and polydispersity index before testing on the MDA-MB231 cell line in a range of assays including cell viability, migration, invasion and gene knock down. Results shRNA-loaded nanoparticles were successfully fabricated and delivered to MDA-MB231 cells in culture, where they effectively released their payload, causing a decrease in both cell invasion and cell migration by knocking down RAN gene expression. Conclusion Results indicate the anti-RAN shRNA-loaded nanoparticles deliver and release biological payload to MDA-MB231 cells in culture. This works paves the way for further investigations into the possible use of anti-RAN * SusanHawthorne [email protected] 1 2 3 School of Pharmacy and Pharmaceutical Sciences, Ulster University, Cromore Road, Coleraine, Co. Londonderry BT52 1SA, UK School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Health Sciences Building, 97 Lisburn Road, Belfast BT9 7BL, UK Institute of Cancer Therapeutics, ICT building, University of Bradford, Richmond Road, Bradford, England BD7 1DP,UK shRNA-loaded NP formulations for the treatment of breast cancer in vivo

Meeting unique requirements: Community consultation and public disclosure for research in emergency setting using exception from informed consent

BackgroundException from informed consent (EFIC) regulations for research in emergency settings contain unique requirements for community consultation and public disclosure. These requirements address ethical challenges intrinsic to this research context. Multiple approaches have evolved to accomplish these activities that may reflect and advance different aims. This scoping review was designed to identify areas of consensus and lingering uncertainty in the literature.MethodsScoping review methodology was used. Conceptual and empirical literature related to community consultation and public disclosure for EFIC research was included and identified through a structured search using Embase, HEIN Online, PubMed, and Web of Science. Data were extracted using a standardized tool with domains for major literature categories.ResultsAmong 84 manuscripts, major domains included conceptual or policy issues, reports of community consultation processes and results, and reports of public disclosure processes and results. Areas of consensus related to community consultation included the need for a two‐way exchange of information and use of multiple methods. Public acceptance of personal EFIC enrollment is commonly 64% to 85%. There is less consensus regarding how to assess attitudes, what “communities” to prioritize, and how to determine adequacy for individual projects. Core goals of public disclosure are less well developed; no metrics exist for assessing adequacy.ConclusionsMultiple methods are used to meet community consultation and public disclosure requirements. There remain no settled norms for assessing adequacy of public disclosure, and there is lingering debate about needed breadth and depth of community consultation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170817/1/acem14264_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170817/2/acem14264.pd