UCL Discovery Stage
UCL home » Library Services » Electronic resources » UCL Discovery Stage

Investigation of unique dependencies of cells lacking the PTEN tumour suppressor gene

Vlachogiannis, G; (2013) Investigation of unique dependencies of cells lacking the PTEN tumour suppressor gene. Doctoral thesis , UCL (University College London).

Full text not available from this repository.

Abstract

Over the past ten years significant effort has been put in the identification of pharmacological targets that facilitate the selective targeting of cancer cells. The concept of synthetic lethality in combination with RNA interference (RNAi) technology provides an attractive platform for the identification of such drug targets. With this in mind I designed, set up, and executed a large-scale siRNA screen aiming at identifying genes that exhibit a synthetic lethal relationship with loss of the PI3K/AKT signalling cascade negative regulator PTEN. A PTEN-isogenic cell system derived from the breast epithelial cell line MCF10A was employed in this study, and screened with a siRNA library against the “Druggable genome”. Putative hits exhibiting a potential synthetic lethal relationship with loss of PTEN were identified by differential Z-score analysis, and validated in a panel of breast cancer cell lines segregated based on their PTEN status. This analysis identified several PTEN-loss synthetic lethal candidate genes whose further evaluation may reveal new insights in the biology of PTEN null cancer cells. The functional mechanism underlying one of the identified PTEN-loss synthetic lethal putative hits (CYTH1/PSCD1) was investigated in detail. Knockdown of CYTH1 selectively induced apoptosis in the PTEN-/- MCF10A cells, and biochemical and genetic evidence supported a potential synthetic lethal relationship with PI3K/AKT pathway activation due to loss of PTEN. Although definite confirmation that CYTH1 was the sole target mediating the identified PTEN-loss synthetic lethal interaction was not obtained, further investigation on the exact nature of the described PTEN-loss synthetic lethal relationship may have the potential to uncover previously unknown vulnerabilities of PTEN-deficient cancer cells that could be pharmacologically exploited.

Type: Thesis (Doctoral)
Title: Investigation of unique dependencies of cells lacking the PTEN tumour suppressor gene
Language: English
Keywords: PTEN, synthetic lethality
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery-pp.ucl.ac.uk/id/eprint/1395122
Downloads since deposit
308Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item