Investigating PLEKHS1 adaptor function in PI3K signalling and human cancer biology
type: CreativeWork
description: The Class-IA PI3K signalling pathway regulates key anabolic cellular processes including proliferation, survival, growth and metabolism. Oncogenic hyperactivation of the pathway occurs across tumour types, commonly via genetic alterations in key pathway genes (e.g., *PIK3CA*, *PTEN*). Despite extensive research, the primary drivers of healthy or oncogenic PI3K signalling *in vivo* are largely unknown and PI3K pathway inhibitors show limited clinical benefit in solid tumours. Identifying upstream regulators of oncogenic PI3K activation can reveal novel therapeutic targets and/or biomarkers. Previously generated *in vivo* interactomics data identified the RTK/IRS network as the primary driver of homeostatic PI3K activation in healthy mouse prostate, and PLEKHS1 as the primary driver of oncogenic PI3K activation in cancerous, PTEN-null mouse prostate. PTEN phosphatase is a tumour-suppressor and inactivated commonly in prostate cancers. PLEKHS1 is otherwise a poorly characterised protein. This thesis presents research investigating the relevance and mechanisms of PLEKHS1 adaptor protein function to oncogenic PI3K pathway remodelling in human cancers, with a focus on prostate cancer. TCGA pan-cancer analyses report *IRS1* downregulation and *PLEKHS1* upregulation in several primary carcinomas, compared to healthy tissue. In prostate, endometrial and breast cancers, *PLEKHS1* expression correlates with PI3K pathway activation and alterations in key pathway genes (*PTEN*, *PIK3CA*). In castration-resistant prostate cancer, *PLEKHS1* is under-expressed in neuroendocrine cancers, compared to adenocarcinomas. ChIP-Seq datasets report binding of key prostate cancer transcriptional regulators to the *PLEKHS1* locus (e.g., AR, FOXA1). To investigate PLEKHS1 adaptor protein function *in vitro*, LNCaP prostate cancer cell line is used due to its PTEN-null status and PI3K pathway hyperactivation. Transient over-expression of PLEKHS1 in LNCaP cells generates a robust PIP3 response v…
abstract: The Class-IA PI3K signalling pathway regulates key anabolic cellular processes including proliferation, survival, growth and metabolism. Oncogenic hyperactivation of the pathway occurs across tumour types, commonly via genetic alterations in key pathway genes (e.g., *PIK3CA*, *PTEN*). Despite extensive research, the primary drivers of healthy or oncogenic PI3K signalling *in vivo* are largely unknown and PI3K pathway inhibitors show limited clinical benefit in solid tumours. Identifying upstream regulators of oncogenic PI3K activation can reveal novel therapeutic targets and/or biomarkers. Previously generated *in vivo* interactomics data identified the RTK/IRS network as the primary driver of homeostatic PI3K activation in healthy mouse prostate, and PLEKHS1 as the primary driver of oncogenic PI3K activation in cancerous, PTEN-null mouse prostate. PTEN phosphatase is a tumour-suppressor and inactivated commonly in prostate cancers. PLEKHS1 is otherwise a poorly characterised protein. This thesis presents research investigating the relevance and mechanisms of PLEKHS1 adaptor protein function to oncogenic PI3K pathway remodelling in human cancers, with a focus on prostate cancer. TCGA pan-cancer analyses report *IRS1* downregulation and *PLEKHS1* upregulation in several primary carcinomas, compared to healthy tissue. In prostate, endometrial and breast cancers, *PLEKHS1* expression correlates with PI3K pathway activation and alterations in key pathway genes (*PTEN*, *PIK3CA*). In castration-resistant prostate cancer, *PLEKHS1* is under-expressed in neuroendocrine cancers, compared to adenocarcinomas. ChIP-Seq datasets report binding of key prostate cancer transcriptional regulators to the *PLEKHS1* locus (e.g., AR, FOXA1). To investigate PLEKHS1 adaptor protein function *in vitro*, LNCaP prostate cancer cell line is used due to its PTEN-null status and PI3K pathway hyperactivation. Transient over-expression of PLEKHS1 in LNCaP cells generates a robust PIP3 response v…
author: Anwar, Arqum
language: eng
keywords: Cancer, HCC70, IRS1, LNCaP, organoids, PI3K, PLEKHS1, Prostate Cancer, PTEN, SRC
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/81971554-d0d5-4e78-85e8-7a2a66ace835/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-09-08
date modified: 2026-07-22T22:24:20Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.104491