학술논문
Expression and Localization of Ferritin-Heavy Chain Predicts Recurrence for Breast Cancer Patients with a BRCA1/2 Mutation
Document Type
Academic Journal
Author
Qu, Shuoying; Timmermans, A. Mieke; Heemskerk-Gerritsen, Bernadette A. M.; Trapman-Jansen, Anita M. A. C.; Broeren-Foekens, Renée; Prager-van der Smissen, Wendy J. C.; El Hassnaoui, Hoesna; van Tienhoven, Tim; Bes-Stobbe, Claudia K.; Westenend, Pieter J.; van Deurzen, Carolien H. M.; Martens, John W. M.; Hooning, Maartje J.; Hollestelle, Antoinette
Source
Cancers. December 2023, Vol. 16 Issue 1
Subject
Language
English
ISSN
2072-6694
Abstract
Author(s): Shuoying Qu [1,†]; A. Mieke Timmermans [1,†]; Bernadette A. M. Heemskerk-Gerritsen [1]; Anita M. A. C. Trapman-Jansen [1]; Renée Broeren-Foekens [1]; Wendy J. C. Prager-van der Smissen [1]; Hoesna [...]
Ferritin is a ferroxidase, which protects cellular components from the potentially toxic effects of free iron. The expression and localization of ferritin-heavy chain (FTH1), the catalytic subunit of ferritin, was shown to predict survival for triple-negative breast cancer (BC) patients and be related to T-cell response. Here, we studied the association between FTH1 and time to survival in primary BCs from 222 BRCA1/2 mutation carriers. We found that nuclear, but not cytoplasmic, localization of FTH1 expression was associated with a shorter time to recurrence. In a subset of 51 BRCA1/2 mutation carriers, we evaluated the relation between localization and expression of FTH1 and T-cell response. However, we did not detect any association between FTH1 and the amount or composition of CD8+ cytotoxic, CD4+ helper, or FOXP3+ regulatory T cells. Further research is necessary to unravel the mechanism by which nuclear FTH1 influences the clinical outcome of BRCA1/2-associated BC patients. The ferritin-heavy chain (FTH1) is the catalytic subunit of the ferroxidase ferritin, which prevents oxidative DNA damage via intracellular iron storage. FTH1 was shown to be a prognostic marker for triple-negative breast cancer (BC) patients and associated with an enrichment of CD8+ effector T cells. However, whether the expression and localization of FTH1 are also associated with clinical outcome in other BC subtypes is unknown. Here, we investigated the association of FTH1 with time to survival in BCs from 222 BRCA1/2 mutation carriers by immunohistochemistry on tissue microarrays. In addition, for 51 of these patients, the association between FTH1 and specific subsets of T cells was evaluated on whole slides using automatic scoring algorithms. We revealed that nuclear FTH1 (nFTH1) expression, in multivariable analyses, was associated with a shorter disease-free (HR = 2.71, 95% CI = 1.49–4.92, p = 0.001) and metastasis-free survival (HR = 3.54, 95% CI = 1.45–8.66, p = 0.006) in patients carrying a BRCA1/2 mutation. However, we found no relation between cytoplasmic FTH1 expression and survival of BRCA1/2 mutation carriers. Moreover, we did not detect an association between FTH1 expression and the amount of CD45+ (p = 0.13), CD8+ (p = 0.18), CD4+ (p = 0.20) or FOXP3+ cells (p = 0.17). Consequently, the mechanism underlying the worse recurrence-free survival of nFTH1 expression in BRCA1/2 mutation carriers needs further investigation.
Ferritin is a ferroxidase, which protects cellular components from the potentially toxic effects of free iron. The expression and localization of ferritin-heavy chain (FTH1), the catalytic subunit of ferritin, was shown to predict survival for triple-negative breast cancer (BC) patients and be related to T-cell response. Here, we studied the association between FTH1 and time to survival in primary BCs from 222 BRCA1/2 mutation carriers. We found that nuclear, but not cytoplasmic, localization of FTH1 expression was associated with a shorter time to recurrence. In a subset of 51 BRCA1/2 mutation carriers, we evaluated the relation between localization and expression of FTH1 and T-cell response. However, we did not detect any association between FTH1 and the amount or composition of CD8+ cytotoxic, CD4+ helper, or FOXP3+ regulatory T cells. Further research is necessary to unravel the mechanism by which nuclear FTH1 influences the clinical outcome of BRCA1/2-associated BC patients. The ferritin-heavy chain (FTH1) is the catalytic subunit of the ferroxidase ferritin, which prevents oxidative DNA damage via intracellular iron storage. FTH1 was shown to be a prognostic marker for triple-negative breast cancer (BC) patients and associated with an enrichment of CD8+ effector T cells. However, whether the expression and localization of FTH1 are also associated with clinical outcome in other BC subtypes is unknown. Here, we investigated the association of FTH1 with time to survival in BCs from 222 BRCA1/2 mutation carriers by immunohistochemistry on tissue microarrays. In addition, for 51 of these patients, the association between FTH1 and specific subsets of T cells was evaluated on whole slides using automatic scoring algorithms. We revealed that nuclear FTH1 (nFTH1) expression, in multivariable analyses, was associated with a shorter disease-free (HR = 2.71, 95% CI = 1.49–4.92, p = 0.001) and metastasis-free survival (HR = 3.54, 95% CI = 1.45–8.66, p = 0.006) in patients carrying a BRCA1/2 mutation. However, we found no relation between cytoplasmic FTH1 expression and survival of BRCA1/2 mutation carriers. Moreover, we did not detect an association between FTH1 expression and the amount of CD45+ (p = 0.13), CD8+ (p = 0.18), CD4+ (p = 0.20) or FOXP3+ cells (p = 0.17). Consequently, the mechanism underlying the worse recurrence-free survival of nFTH1 expression in BRCA1/2 mutation carriers needs further investigation.