Abstract 1739: Diminished SKP1 or CUL1 expression induces chromosome instability in high-grade serous ovarian cancer precursor cells

Abstract

Abstract High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype as well as the most lethal. High mortality rates associated with HGSOC are in part due to a lack of reliable early detection methods and effective therapies. Importantly, chromosome instability (CIN; an increased rate of chromosome gains or losses), is causally implicated in cancer development, progression, and resistance to treatment, and is just beginning to be evaluated in an HGSOC context. Overexpression of Cyclin E1 protein induces CIN and genomic amplification contributes to HGSOC pathogenesis in 20% of HGSOC patients. Cyclin E1 protein levels are normally regulated in a cell cycle-dependent manner by the SCF (SKP1-CUL1-FBOX) complex, an E3 ubiquitin ligase that targets substrates for proteolytic degradation. In cases where genomic amplification is absent, we hypothesize that loss of SCF complex function stemming from diminished expression of individual SCF complex components underlies increases in Cyclin E1 levels and induces CIN. The current study focuses on the SCF complex components SKP1 and CUL1 and characterizes their role in early HGSOC pathogenesis within a fallopian tube secretory epithelial cell model (FT; a cell of origin for HGSOC). Using siRNA-based approaches, we show that diminished SKP1 and CUL1 expression results in increased Cyclin E1 protein levels in FT cells. Using quantitative imaging microscopy techniques, we further identify statistically significant changes in CIN-associated phenotypes within the silenced populations, including changes in nuclear areas, increases in micronucleus formation (i.e. small DNA-containing bodies outside of the primary nucleus), and increases in numerical chromosome abnormalities identified in mitotic chromosome spreads. Thus, the current study explores the early origins of HGSOC and identifies SKP1 and CUL1 as two promising new molecular players that may contribute to CIN to drive FT cell transformation, drug resistance and disease recurrence. Citation Format: Chloe C. Lepage, Mark W. Nachtigal, Kirk J. McManus. Diminished SKP1 or CUL1 expression induces chromosome instability in high-grade serous ovarian cancer precursor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1739.