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Characterizing the roles of APC2 protein in ovarian homeostasis and tumourigenesis

Mohamed, Noha-Ehssan 2017. Characterizing the roles of APC2 protein in ovarian homeostasis and tumourigenesis. PhD Thesis, Cardiff University.

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Abstract

Canonical WNT signalling plays a critical role in the regulation of ovarian development during embryogenesis; dysregulation of this pathway in adult ovary is associated with subfertility and tumourigenesis. The aim of the current study was to elucidate the previously unexplored roles of Adenomatous polyposis coli 2 (APC2), a WNT signalling pathway regulator, in the ovary using an Apc2 constitutive knockout mouse. For the first time, the current work demonstrated essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. In early adulthood, APC2-deficiency resulted in WNT signalling activation and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which was not rescued by administration of gonadotrophins. The current study provides fundamental new knowledge on the role of APC2 in ovarian tumourigenesis. APC2-deficiency (on the background of a hypomorph Apc- allele) resulted in a predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and expression of a histologic pattern and molecular signature seen in human adult GCTs. Hence, APC2 has an important tumour-suppressor activity within ovarian granulosa cells. However, APC2 is dispensable for ovarian surface epithelium (OSE) homeostasis. APC2 loss on its own, or combined with PTEN or APC loss in the OSE, failed to cause tumour development. Introducing APC2-deficiency to an ovarian endometrioid adenocarcinoma (OEA) mouse model, driven by loss of PTEN and APC in the OSE, resulted in early initiation of tumourigenesis, but attenuated tumour growth. This attenuation was accompanied by squamous metaplasia, decreased mitosis, decreased p-ERK1/2 expression and disrupted immune/inflammatory signalling. Thus, for the first time, an APC2 functional dualism in initiation and progression of WNT-driven OEA in mice is reported. RNA sequence analysis unraveled 2 transcripts (HAL and HUNK) associated with OEA progression and should be considered for future research.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
R Medicine > RB Pathology
Uncontrolled Keywords: APC2- female/ovarian subfertility- ovarian granulosa cell tumour- ovarian endometrioid adenocarcinoma- ovarian surface epithelium- genetically engineered mouse model
Funders: Egyptian missions sector (Egyptian educational office in London)
Date of First Compliant Deposit: 17 October 2017
Last Modified: 01 Nov 2017 14:57
URI: http://orca.cf.ac.uk/id/eprint/105634

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