Subcellular localization of FANCD2 is associated with survival in ovarian carcinoma.

Sonali Joshi,Jeong Y Lim,Tanja Pejovic,Yukie Bean,Shannon Mcweeney,Nadja Pejovic,Adam Krieg,Shawn Campbell,Paulette Mhawech-Fauceglia

doi:10.18632/oncotarget.27437

Abstract

Objective: Ovarian cancer is a leading cause of death from gynecological cancers. Late diagnosis and resistance to therapy results in mortality and effective screening is required for early diagnosis and better treatments. Expression of the Fanconi Anemia complementation group D2 protein (FANCD2) is reduced in ovarian surface epithelial cells (OSE) in patients with ovarian cancer. FANCD2 has been studied for its role in DNA repair; however multiple studies have suggested that FANCD2 has a role outside the nucleus. We sought to determine whether subcellular localization of FANCD2 correlates with patient outcome in ovarian cancer.Methods: We examined the subcellular localization of FANCD2 in primary OSE cells from consenting patients with ovarian cancer or a normal ovary. Ovarian tissue microarray was stained with anti-FANCD2 antibody by immunohistochemistry and the correlation of FANCD2 localization with patient outcomes was assessed. FANCD2 binding partners were identified by immunoprecipitation of cytoplasmic FANCD2.Results: Nuclear and cytoplasmic localization of FANCD2 was observed in OSEs from both normal and ovarian cancer patients. Patients with cytoplasmic localization of FANCD2 (cFANCD2) experienced significantly longer median survival time (50 months), versus patients without cytoplasmic localization of FANCD2 (38 months; p < 0.05). Cytoplasmic FANCD2 was found to bind proteins involved in the innate immune system, cellular response to heat stress, amyloid fiber formation and estrogen mediated signaling.Conclusions: Our results suggest that the presence of cytoplasmic FANCD2 modulates FANCD2 activity resulting in better survival outcome in ovarian cancer patients.

Highlights

Stage ovarian cancer is often characterized by a lack of specific symptoms leading to a late stage diagnosis [1]
Nuclear and cytoplasmic localization of Fanconi Anemia complementation group D2 protein (FANCD2) was observed in ovarian surface epithelial cells (OSE) from both normal and ovarian cancer patients
Our results suggest that the presence of cytoplasmic FANCD2 modulates FANCD2 activity resulting in better survival outcome in ovarian cancer patients

Summary

Introduction

Stage ovarian cancer is often characterized by a lack of specific symptoms leading to a late stage diagnosis [1]. Platinum resistance is observed in ~25% of patients within 6 months [3] and at present the 5 year survival rate for ovarian cancer is 47% [4]. There is a pressing need to develop a better understanding of the molecular basis of ovarian cancer to provide the most beneficial clinical prospects, increase patient survival and decrease disease incidence. Genetic and epigenetic alterations of the homologous recombination (HR) repair pathway are observed in 50% of ovarian tumors [5]. Lack of HR repair sensitizes ovarian tumors to platinum-based therapeutics and alteration of DNA repair genes can modulate tumor characteristics and response to therapy [8]

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Results

Conclusion