APC2 is Critical for Ovarian WNT Signalling Control, Fertility and Tumour Suppression

Abstract

Canonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate for the first time using constitutive APC2-knockout (Apc2-/-) mice, essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. APC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs. Hence, APC2 has an important tumour-suppressor activity within ovarian granulosa cells, most likely due to its role in regulating WNT-signalling. Importantly, given that the APC2-deficient tumours recapitulate the molecular signature and histological features of human adult GCTs, this APC2-deficient mouse has excellent potential as a pre-clinical model to study ovarian tumour biology and for therapeutic testing.