Abstract 2780: High nuclear FTH1 protein expression predicts early disease recurrence for BRCA1/2 mutation carriers

Abstract

Abstract FTH1 is a 21kD subunit of the ferritin complex, which is involved in intracellular iron storage. In a previous study we found that FTH1 proteins can be located either in the cytoplasm or nucleus and, depending on its cellular localization, is associated with good or poor prognosis in triple negative breast cancer (TNBC). Furthermore, cytoplasmic localization of cFTH1 was associated with an increased anti-tumor (CD8+) T-cell / tumor-promoting (CD4+) T-cell ratio suggesting an immune modulatory role for FTH1. In the current study we have assessed the prognostic value of FTH1 expression for BRCA1/2 mutation carriers. FTH1 proteins were visualized by immunohistochemistry on a tissue microarray containing primary breast cancer specimens from 222 BRCA1/2 mutation carriers that were diagnosed between 1982 and 2008. Primary breast cancers from BRCA1 carriers were predominantly of the TNBC subtype, whereas primary breast cancers from BRCA2 mutation carriers were mainly ER-positive. The association between FTH1 expression and clinical outcome was evaluated by a Cox proportional hazards regression model using left truncation to adjust for study inclusion bias. The median follow-up time of the study was 9.2 years. High nuclear FTH1 (nFTH1), but not cytoplasmic FTH1 (cFTH1), was associated with decreased metastasis-free and disease-free survival as compared with low nFTH1 (multivariable HR=3.54, 95% CI=1.45-8.66, P=0.0056 adjusted for tumor size and nodal status; multivariable HR=2.71, 95% CI=1.49-4.92, P=0.0011 adjusted for tumor size). Neither nFTH1 nor cFTH1 were associated with breast cancer-specific or overall survival. This suggests that high nFTH1 expression in primary breast cancer predicts earlier disease recurrence for BRCA1/2 mutation carriers. Since we had observed that CD4+:CD8+ T-cell ratios were increased among TNBCs with high nFTH1, we hypothesize that nFTH1 promotes recruitment of immune suppressive CD4+/FOXP3+ regulatory T-cells in TNBC and BRCA1/2-associated tumors, suppressing CD4+/FOXP3- and CD8+ T-cell anti-tumor immunity. Citation Format: Antoinette Hollestelle, Mieke Timmermans, Renée Broeren-Foekens, Anita Trapman - Jansen, Carolien H. van Deurzen, Arzu Umar, John W. Martens, Maartje Hooning. High nuclear FTH1 protein expression predicts early disease recurrence for BRCA1/2 mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2780. doi:10.1158/1538-7445.AM2017-2780