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An Iron Regulatory Gene Signature Predicts Outcome in Breast Cancer
Open accessPublished version of a preprint
Abstract
Changes in iron regulation characterize the malignant state. However, the pathways that effect these changes and their specific impact on prognosis remain poorly understood. We capitalized on publicly available microarray datasets comprising 674 breast cancer cases to systematically investigate how expression of genes related to iron metabolism is linked to breast cancer prognosis. Of 61 genes involved in iron regulation, 49% were statistically significantly associated with distant metastasis-free survival. Cases were divided into test and training cohorts, and the supervised principal component method was used to stratify cases into risk groups. Optimal risk stratification was achieved with a model comprising 16 genes, which we term the iron regulatory gene signature (IRGS). Multivariable analysis revealed that the IRGS contributes information not captured by conventional prognostic indicators (HR = 1.61; 95% confidence interval: 1.16-2.24; P = 0.004). The IRGS successfully stratified homogeneously treated patients, including ER+ patients treated with tamoxifen monotherapy, both with (P = 0.006) and without (P = 0.03) lymph node metastases. To test whether multiple pathways were embedded within the IRGS, we evaluated the performance of two gene dyads with known roles in iron biology in ER+ patients treated with tamoxifen monotherapy (n = 371). For both dyads, gene combinations that minimized intracellular iron content [anti-import: TFRC(Low)/HFE(High); or pro-export: SLC40A1 (ferroportin)(High)/HAMP(Low)] were associated with favorable prognosis (P < 0.005). Although the clinical utility of the IRGS will require further evaluation, its ability to both identify high-risk patients within traditionally low-risk groups and low-risk patients within high-risk groups has the potential to affect therapeutic decision making.
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“Intriguingly, a significant association between almost 50% of genes involved in iron metabolism and breast cancer prognosis has been observed (Miller et al., 2011).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Miller et al., 2011
In the citing paper
“Interestingly, large amounts of hepcidin are found both within the tumor microenvironment and systemically in cancer patients [73,74,75,76].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [74]
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Iron and cancer: more ore to be mined
Torti, S. V., & Torti, F. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3495 · Cited by 1,621
Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease
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BackgroundFerroptosis is induced following siramesine and lapatinib treatment of breast cancer cells
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“However in breast cancer cells, down regulation of ferroportin promotes breast cancer growth and is correlated with poor prognosis.(39) This suggests iron regulation is altered in breast cancer and could be a target for cancer therapy.”
BackgroundIron addiction: a novel therapeutic target in ovarian cancer
Basuli, D., Tesfay, L., Deng, Z., Paul, B., Yamamoto, Y., Ning, G., Xian, W., McKeon, F., Lynch, M. L., Crum, C. P., et al. (2017) · Oncogene · doi:10.1038/onc.2017.11 · Cited by 469
“An iron acquisition phenotype has now been reported in a number of cancers: breast(34, 35), glioblastoma(36), prostate(37), and others(11).”
BackgroundTorti, S. V., Manz, D. H., Paul, B. T., Blanchette-Farra, N., & Torti, F. M. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082117-051732 · Cited by 426
Metadata
- Authors
- Miller, L. D., Coffman, L. G., Chou, J. W., Black, M. A., Bergh, J., D'Agostino, R., Torti, S. V., & Torti, F. M.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Torti, Frank M.
- Venue
- Cancer Research
- Published
- 2011-10-30
- Volume
- 71
- Issue
- 21
- Pages
- 6728-6737
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3206152
- OpenAlex
- W2101427112
- Cited by
- 202
- References
- 38
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 3 · 2023: 14 · 2022: 15 · 2021: 26 · 2020: 19 · 2019: 19 · 2018: 9 · 2017: 20 · 2016: 17 · 2015: 8 · 2014: 16 · 2013: 15 · 2012: 11
- FWCI
- 11.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA012197)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071892, R37 DK42412, R37DK042412)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- breast cancer, iron metabolism, prognostic gene signature, distant metastasis-free survival, risk stratification, estrogen receptor-positive breast cancer, ferroportin, SLC40A1, HFE gene, transferrin receptor, hepcidin, gene expression
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Estrogens, Female, Humans, Iron, Lymphatic Metastasis, Models, Genetic, Neoplasms, Hormone-Dependent, Prognosis, Tamoxifen, Survival Analysis, Treatment Outcome, Chemotherapy, Adjuvant, Disease-Free Survival, Antineoplastic Agents, Hormonal, Estrogen Receptor Modulators, Gene Expression Profiling
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