Cited by 202Ferroptosis and cancer prognosisBreast Cancer Treatment StudiesIron Metabolism and Disorders

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An Iron Regulatory Gene Signature Predicts Outcome in Breast Cancer

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Miller, Lance D., Coffman, Lan G., Chou, Jeff W., Black, Michael A., Bergh, Jonas, D'Agostino, Ralph, Torti, Suzy V., Torti, Frank M.·2011·Cancer Research

DOI 10.1158/0008-5472.can-11-1870PMC PMC3206152

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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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“org Cancer Res; 71(21) November 1, 2011 OF3”
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Background
Global analysis of iron metabolism‐related genes identifies potential mechanisms of gliomagenesis and reveals novel targets
Zhang, J., Zhao, L., Xuan, S., Liu, Z., Weng, Z., Wang, Y., Dai, K., Gu, A., & Zhao, P. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14386 · Cited by 7
Iron metabolism in breast cancer: knowledge and future
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Iron and Cancer
Torti, S. V., Tesfay, L., & Torti, F. M. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-92033-2_18 · Cited by 6
Iron and metabolic rewiring in cancer
Ciscar, M., Rodríguez-Santana, C., & Santana-Codina, N. (2026) · Oncogenesis · doi:10.1038/s41389-025-00595-w · Cited by 11
“Elevated iron levels and altered iron metabolism correlate with drug resistance and poor outcomes in chemotherapy-treated patients [32, 92, 93].”
Detection of Ferritin Expression in Soft Tissue Sarcomas With MRI: Potential Implications for Iron Metabolic Therapy.
Petronek, M. S., Tomanek‐Chalkley, A., Monga, V., Milhem, M. M., Miller, B. J., Magnotta, V. A., & Allen, B. G. (2022) · PubMed Central · Cited by 6
The progress in the relationship between trace elements and acute lymphoblastic leukemia
Wang, J., Huang, P. Y., Lang, C., Luo, Y., He, Z., & Chen, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1145563 · Cited by 6
“Ferrum can promote the production of reactive oxygen species, ferrum overload destroys the body’s immune surveillance of malignant cells, and ferrum overload antagonizes other micronutrients (Rouault and Tong, 2008; Miller et al., 2011).”
Background
Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts
Torti, S. V., Lemler, E., & Mueller, B. K. (2016) · Clinical and Experimental Pharmacology · doi:10.4172/2161-1459.1000223 · Cited by 5
Update of the sideroflexin (SLC56) gene family
Katsafadou, A. I., Nebert, D. W., Krupenko, S. A., Thompson, D. C., & Vasiliou, V. (2025) · Human Genomics · doi:10.1186/s40246-025-00779-w · Cited by 5
Hemochromatosis: a model of metal-related human toxicosis
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Cultural and Environmental Factors of Triple-Negative Breast Carcinomas
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“and particularly with regard to the triple-negative phenotype, the study is consistent with other recent findings that almost 50% of gene expression related to iron metabolism has a statistically significant association with risk of breast cancer [52].”
Result
Decoding iron deficiency in cancer: mechanisms, immune modulation, and therapeutic potential
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The role of the C5a-C5aR pathway in iron metabolism and gastric cancer progression
Ni, Q., Yang, H., Rao, H., Zhang, L., Xiong, M., Han, X., Deng, B., Wang, L., Chen, J., & Shi, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1522181 · Cited by 5
“Notably, signi ﬁ cant amounts of hepcidin are found both within the tumor microenvironment and systemically in cancer patients (11, 57 – 59).”
Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis
Guan, Q., Yu, L., Wang, P., Hu, Q., & Tan, C. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.5c00219 · Cited by 4
Divergent iron regulatory states contribute to heterogeneity in breast cancer aggressiveness
Leineweber, W. D., Rowell, M. Z., Ranamukhaarachchi, S. K., Walker, A., Li, Y., Villazon, J. I., Mestre‐Farrera, A., Hu, Z., Yang, J., Shi, L., et al. (2024) · iScience · doi:10.1016/j.isci.2024.110661 · Cited by 6
“Knocking down IRP1/ACO1 signiﬁcantly reduced invasion (Figures 2E–2G and S3), suggesting that the invasive phenotype is indeed dependent on IRP1/ACO1.”
Macroscopic fluorescence lifetime-based Förster resonance energy transfer imaging for quantitative ligand–receptor binding
Rudkouskaya, A., Faulkner, D. E., Sinsuebphon, N., Intes, X., & Barroso, M. (2020) · Elsevier eBooks · doi:10.1016/b978-0-08-102983-1.00012-0 · Cited by 4
Raman hyperspectral imaging of transferrin-bound iron in cancer cells
Khoo, T. C., Tubbesing, K. E., Pham, L. G. C., Desta, H., Sharikova, A. V., Barroso, M., & Khmaladze, A. T. (2019) · Label-free Biomedical Imaging and Sensing (LBIS) · doi:10.1117/12.2511397 · Cited by 3
Association of TMPRSS6 polymorphisms with hematologic parameters, histopathological data and breast cancer risk in Turkish population
Güven, M. F., Mete, M., Trabulus, D. C., Özoran, E., & Erhan, D. (2021) · Meta Gene · doi:10.1016/j.mgene.2021.100941 · Cited by 3
Environmental impact on carcinogenesis under BRCA1 haploinsufficiency
Toyokuni, S., Kong, Y., Motooka, Y., & Akatsuka, S. (2023) · Genes and Environment · doi:10.1186/s41021-023-00258-5 · Cited by 3
“This is based on the fact that both organs are deeply associated with iron metabolism including lactoferrin secretion in milk [71, 72] and ovulation.”
Background
Elevated labile iron in castration–resistant prostate cancer is targetable with ferrous iron–activatable antiandrogen therapy
Gonciarz, R. L., Sakhamuri, S., Hooshdaran, N., Kumar, G., Kim, H., Evans, M. J., & Renslo, A. R. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115110 · Cited by 4
An Iron Regulatory Gene Signature in Breast Cancer: More than a Prognostic Genetic Profile?
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“part of In this study, the authors report on an iron regulatory gene signature (IRGS) that predicts outcome in breast cancer patients [1].”
Background
Image-based quantification of mitochondrial iron uptake via Mitoferrin-2
Polesel, M., Wildschut, M. H. E., Doucerain, C., Kuhn, M. H., Flace, A., Zanetti, L. S., Steck, A., Wilhelm, M., Inglés‐Prieto, Á., Wiedmer, T., et al. (2024) · Mitochondrion · doi:10.1016/j.mito.2024.101889 · Cited by 2
Plasma Iron Levels at Early Breast Cancer Diagnosis Are Associated With Development of Secondary Metastases: A Single-Center Retrospective Cohort Study
Troy, J. D., Fendt, S., Hatse, S., Neven, P., Smeets, A., Laenen, A., & Wildiers, H. P. M. W. (2025) · Breast Cancer Basic and Clinical Research · doi:10.1177/11782234251317070 · Cited by 2
Xanthine oxidoreductase expression is diminished in breast cancer as a response to uric acid mediated chelation of redox active iron
Chapa, M. G., King, R., Dean, Z. W., Maskey, A., Park, R. M., Velayutham, M., Pugacheva, E. N., Woodward, O. M., Webb, B. A., Spitz, D. R., et al. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.06.019 · Cited by 2
Feature extraction via composite scoring and voting in breast cancer
Koch, M., Hanl, M., & Wiese, M. (2012) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2177-3 · Cited by 2
“Especially gene expression signatures of iron metabolism [7] and hypoxia [8] showed striking predictive capabilities.”
Background
Receptor Recognition and Lysosomal Targeting to Enhance Cytotoxicity of Novel Anti-Cancer Agents that Bind Iron and Copper
Merlot, A. M., & Richardson, D. R. (2014) · Vitamins & Minerals · doi:10.4172/2376-1318.1000e125 · Cited by 2
“Moreover, tumor cells have increased iron and copper requirements that are necessary to sustain their generally highly proliferative nature [2-4].”
Background
Evaluation of the expression level of apoptosis and ferroptosis cell death pathways genes in patients with osteosarcoma
Nazem, S., Mirzaei, A., Tavakoli‐Yaraki, M., Najafi, T., Salami, S., Bashash, D., & Shahsavari, Z. (2022) · Gene Reports · doi:10.1016/j.genrep.2022.101506 · Cited by 2
Exploiting KRAS-Driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)Preprint
Jiang, H., Muir, R. K., Gonciarz, R. L., Olshen, A. B., Yeh, I., Hann, B. C., Zhao, N., Wang, Y.-H., Behr, S. C., Evans, M. J., et al. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3581366 · Cited by 2
Gambogic acid-loaded transferrin-modified liposomes enhancing potent ferroptosis in breast cancer
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“Therefore, modifying transferrin on the surface of the preparation can achieve a certain effect of targeting the tumor site, and transferrin can mediate the endocytic uptake of cells 18 .”
Reply to T. Hasegawa et al and I. Gross et al
Leyland-Jones, B. R., Vercammen, E., & Xiu, L. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.68.7681 · Cited by 1
“Particularly in breast cancer, almost 50% of all genes that are involved in the regulation or maintenance of iron metabolism were significantly associated with clinical outcome.(8) We believe these findings may contribute to the cautious use of iron supplementation in patients with cancer.”
Iron and Lipocalin-2 Modulate Cellular Responses in the Tumor Micro-environment of Pancreatic Ductal AdenocarcinomaPreprint
Pita-Grisanti, V., Dangel, A. W., Gumpper, K., Ludwig, A. A., Ueltschi, O., Mo, X. M., Pietrzak, M., Webb, A., Hwang, R. F., Traczek, M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.14.907188 · Cited by 1
SOX7 is downregulated and functions as a tumor suppressive transcription factor in breast cancer
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The Prognostic Capability and Molecular Function of Duodenal Cytochrome B in Breast Cancer
Lemler, D. J. (2016) · OpenCommons at University of Connecticut (University of Connecticut)
Investigating Novel Biological Mechanisms of Head and Neck Cancers
Lenarduzzi, M. (2014) · TSpace (University of Toronto)
Multiple Modes of Hepcidin Regulation in Breast Cancer
Farra, N. (2017) · OpenCommons - UConn (University of Connecticut)
Prognostic Significance of Cellular Iron Metabolism in Breast Cancer
Hassan, A., Faridi, T. A., Tanvir, I., & Rafi, U. (2021) · DIET FACTOR (Journal of Nutritional & Food Sciences) · doi:10.54393/df.v2i2.25
“If the cancer cells not stopped there than they continue travelling in the lymphatic to other parts of the breast [9,10].”
Background
Clinical implications and immunological features of iron metabolism-related gene prognostic signature in breast cancerPreprint
Wang, W., Yu, A., Wang, Z., Guo, H., Yue, C., Li, N., Wang, Y., Gao, S., & Hua, C. (2022) · Research Square · doi:10.21203/rs.3.rs-2317141/v1
Data from Targeting Cellular Iron Homeostasis with Ironomycin in Diffuse Large B-cell Lymphoma
Devin, J., Cañeque, T., Lin, Y., Mondoulet, L., Veyrune, J., Abouladzé, M., Paco, E. G. D., Gadacha, O. K., Cartron, G., Pasero, P., et al. (2023) · doi:10.1158/0008-5472.c.6513636.v1
Data from Targeting Cellular Iron Homeostasis with Ironomycin in Diffuse Large B-cell Lymphoma
Devin, J., Cañeque, T., Lin, Y., Mondoulet, L., Veyrune, J., Abouladzé, M., Paco, E. G. D., Gadacha, O. K., Cartron, G., Pasero, P., et al. (2023) · doi:10.1158/0008-5472.c.6513636
Data from Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models
Bordini, J., Morisi, F., Elia, A. R., Santambrogio, P., Pagani, A., Cucchiara, V., Ghia, P., Bellone, M., Briganti, A., Camaschella, C., et al. (2023) · doi:10.1158/1078-0432.c.6529337
Data from Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models
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Tubacin plus Erastin Treatment Sensitizes Cell Ferroptosis of Triple Negative Breast Neoplasms
吴, 灿. (2023) · Advances in Clinical Medicine · doi:10.12677/acm.2023.1351222
Additional file 1 of High activity and low toxicity of a novel CD71-targeting nanotherapeutic named The-0504 on preclinical models of several human aggressive tumors
Falvo, E., Damiani, V., Conti, G., Boschi, F., Messana, K., Giacomini, P., Milella, M., Laurenzi, V. D., Morea, V., Sala, G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13889356
Additional file 2 of Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression
Heng, B., BILGIN, A. A. B., Lovejoy, D. B., Tan, V. X., Milioli, H. H. Z., Gluch, L., Bustamante, S., Sabaretnam, T., Moscato, P., Lim, C. K., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13151773
Additional file 3 of Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages
Sun, J.-L., Zhang, N.-P., Xu, R.-C., Zhang, G., Liu, Z.-Y., Abuduwaili, W., Wang, F., Yu, X.-N., Shi, X., Song, G.-Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.15178736
Additional file 1 of Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages
Sun, J.-L., Zhang, N.-P., Xu, R.-C., Zhang, G., Liu, Z.-Y., Abuduwaili, W., Wang, F., Yu, X.-N., Shi, X., Song, G.-Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.15178730
Additional file 4 of Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages
Sun, J.-L., Zhang, N.-P., Xu, R.-C., Zhang, G., Liu, Z.-Y., Abuduwaili, W., Wang, F., Yu, X.-N., Shi, X., Song, G.-Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.15178739
Additional file 1 of Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression
Heng, B., BILGIN, A. A. B., Lovejoy, D. B., Tan, V. X., Milioli, H. H. Z., Gluch, L., Bustamante, S., Sabaretnam, T., Moscato, P., Lim, C. K., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13151770
Additional file 2 of Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages
Sun, J.-L., Zhang, N.-P., Xu, R.-C., Zhang, G., Liu, Z.-Y., Abuduwaili, W., Wang, F., Yu, X.-N., Shi, X., Song, G.-Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.15178733

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.
ORCID: Miller, Lance D.
Coffman, Lan G.
Black, Michael A.
Bergh, Jonas
Torti, Suzy V.
Torti, Frank M.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-10-30
Volume: 71
Issue: 21
Pages: 6728-6737
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-11-1870
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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An Iron Regulatory Gene Signature Predicts Outcome in Breast Cancer

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