Abstract A17: FBxW7 duality in ovarian cancer: Novel insight into ovarian cancer pathogenesis
Authors: Dickson Elizabeth Louise , Li Lihua , Leung Samuel , Chow Christine , Vogel Rachel Isaksson , Huntsman David , Gilks C. Blake , Subramanian Subbaya 
Published: August 2014

Rationale: FBxW7 is a tumor suppressor gene that has been shown to be linked to ubiquitin-dependent proteolysis and regulation of the G1-S cell cycle checkpoint. FBxW7 mutations have been implicated in the impaired degradation of NOTCH, JUN, and cMYC, all of which have been demonstrated as key players in the ovarian cancer pathobiology. In this study we characterized the functional and prognostic significance of FBxW7 in ovarian cancer.

Methods: Platinum-sensitive (A2780) and resistant (C200 and SKOV3) ovarian cancer cell lines were utilized, as well as cell lines derived from normal ovarian epithelium (IOSE). Ovarian cancer cell lines were transfected with FBxW7 constructs using Lipofectamine 2000tm. qPCR was performed to determine levels of gene and microRNA expression. Western blot analysis was performed to assess protein levels. Cell proliferation assays and FACS were performed determine cell proliferation and viability. A tissue microarray was used for immunohistochemical staining using FBxW7 antibody. Tissue stains were scored manually. Staining intensities were correlated with patient outcomes to calculate the overall survival and progression-free survival using Kaplan Meier methods and log-rank tests.

Results: Upregulation of FBxW7 in platinum-sensitive cell lines decreases the substrates of FBxW7 ubiquitination, such as cMYC, NOTCH, and JUN. However, similar levels of FBxW7 expression did not decrease these substrate levels in platinum-resistant cell lines. microRNAs associated with stemness and chemoresistance also had differential expression profiles with FBxW7 transient transfection. Cell proliferation assays also highlighted differences between these sensitive and resistant cell lines. For tissue array analysis, 516 samples were used for FBxW7 IHC staining where 206 (40.2%) of samples were with high-grade serous histology. The majority of samples had FBxW7 staining of high intensity (273; 52.9%). There was no relationship between overall survival or progression-free survival and FBxW7 tissue staining in the total group. However, when analyzing only the high-grade serous histology, there was a trend of increased expression of FBxW7 being associated with better progression-free survival (p=0.051).

Conclusions: Our studies suggest that FBxW7 have a dual role in ovarian cancer, having less effect on those cell lines associated with chemoresistance and stemness. In ovarian tumor tissues, there was a trend for elevated levels of FBxW7 expression and better progression free survival. Further studies on FBxW7 and its role in ovarian cancer pathogenesis are warranted.

Citation Format: Elizabeth Louise Dickson, Lihua Li, Samuel Leung, Christine Chow, Rachel Isaksson Vogel, David Huntsman, C. Blake Gilks, Subbaya Subramanian. FBxW7 duality in ovarian cancer: Novel insight into ovarian cancer pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A17.