A New Mouse Model for the Study of Human Breast Cancer Metastasis

Breast cancer is the most common cancer in women, and this prevalence has a major impact on health worldwide. Localized breast cancer has an excellent prognosis, with a 5-year relative survival rate of 85%. However, the survival rate drops to only 23% for women with distant metastases. To date, the study of breast cancer metastasis has been hampered by a lack of reliable metastatic models. Here we describe a novel in vivo model using human breast cancer xenografts in NOD scid gamma (NSG) mice; in this model human breast cancer cells reliably metastasize to distant organs from primary tumors grown within the mammary fat pad. This model enables the study of the entire metastatic process from the proper anatomical site, providing an important new approach to examine the mechanisms underlying breast cancer metastasis. We used this model to identify gene expression changes that occur at metastatic sites relative to the primary mammary fat pad tumor. By comparing multiple metastatic sites and independent cell lines, we have identified several gene expression changes that may be important for tumor growth at distant sites

Integrated Functional, Gene Expression and Genomic Analysis for the Identification of Cancer Targets

The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer

Reproducibility, collaboration & new ways of doing research

Presented at the National data integrity conference: enabling research: new challenges & opportunities held on May 7-8, 2015 at Colorado State University, Fort Collins, Colorado. Researchers, administrators and integrity officers are encountering new challenges regarding research data and integrity. This conference aims to provide attendees with both a high level understanding of these challenges and impart practical tools and skills to deal with them. Topics will include data reproducibility, validity, privacy, security, visualization, reuse, access, preservation, rights and management.Elizabeth Iorns is the Co-Founder & CEO of Science Exchange. Dr. Iorns conducted her doctoral training in Cancer Biology at the Institute of Cancer Research, London, U.K. under the supervision of Professor Alan Ashworth, before completing a postdoctoral fellowship at the University of Miami under the mentorship of Professor Marc Lippman. Her research has focused on identifying mechanisms of breast cancer development and progression. The mission of Science Exchange is to improve the efficiency of scientific research by making it easy for researchers to access resources and experimental expertise at any research institution. Dr. Iorns co-founded Science Exchange in 2011 based on her own difficulties accessing core facility capabilities and collaborations outside her home university. To solve this they have created a central database of scientific services offered by more than 1000 core facilities and commercial providers.PowerPoint presentation given on May 8, 2015

Reproducibility Initiative: Lynn et al replication

Replication attempt: “Effect of BMAP-28 Antimicrobial Peptides on Leishmania major Promastigote and Amastigote Growth: Role of Leishmanolysin in Parasite Survival

High Throughput Functional Analysis for the Identification of Breast Cancer Targets

Endocrine therapies, which inhibit estrogen receptor a (ERa) signalling, are the most common and effective treatment for ERa positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance. The precise mechanisms underlying endocrine therapy resistance remain incompletely understood and further work is therefore required to identify potential therapeutic targets to inhibit the development of resistance, as well as to identify alternative novel targets for therapy. In this thesis, an RNA interference (RNAi) screen was used to identify modifiers of sensitivity to the most commonly used endocrine therapy, tamoxifen. CDKlO was identified as an important determinant of resistance and was investigated further. CDKlO silencing was shown to activate the MAPK signalling pathway, circumventing the reliance of breast cancer cells upon estrogen signalling. Patients with ERa positive breast tumours that express low levels ofCDKlO were shown to relapse early on tamoxifen and methylation of the CDKlO promoter was observed in a significant proportion of patients, suggesting a mechanism for loss of CDKl 0 expression in tamoxifen resistant tumours. By suppressing gene expression, RNAi, to a certain extent, models the pharmacological inhibition of a target protein. Parallel small molecule screens were performed alongside the RNAi screen to identify small molecule inhibitors that sensitise to tamoxifen. Both the RNAi and small molecule screens identified the PDKl pathway as a potential target for sensitisation. The mechanisms underlying tamoxifen sensitisation were examined. To determine novel therapeutic targets for cancer, genes that are critical to the survival of tumour cells but which are largely redundant in normal cells must be identified. Parallel RNAi screens in cancer cell lines were used to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes potentially constitute selectively lethal targets for cancer therapy. This approach was combined with gene expression and genomic analysis, allowing the identification of novel functionally important therapeutic targets, including WEEl. WEEl was essential for the viability ofWEEl overexpressing cancer cell lines and a subgroup of breast tumours that overexpress WEEl was identified, suggesting WEEl could be a therapeutic target for breast cancer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo