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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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“To examine the clinical relevance of this discovery, we analyzed SOX7 expression in an international metacohort (BrCa759) that consisted of six microarrays with data from 759 breast cancer patients.(33) The SOX7 intensity detected by the two probes 224013_s_at and 228698_at in these arrays was highly correlated (Pears…”
MethodHeng, B., BILGIN, A. A. B., Lovejoy, D. B., Tan, V. X., Milioli, H. H., Gluch, L., Bustamante, S., Sabaretnam, T., Moscato, P., Lim, C. K., et al. (2020) · Breast Cancer Research · doi:10.1186/s13058-020-01351-1 · Cited by 61
Iron homeostasis and anemia markers in early breast cancer
Lamy, P., Durigova, A., & Jacot, W. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.04.011 · Cited by 60
Pogribny, I. P., Tryndyak, V., Pogribna, M., Shpyleva, S., Surratt, G., da Costa, G. G., & Beland, F. A. (2013) · International Journal of Oncology · doi:10.3892/ijo.2013.1855 · Cited by 57
Deng, Z., Manz, D. H., Torti, S. V., & Torti, F. M. (2017) · Oncotarget · doi:10.18632/oncotarget.19288 · Cited by 58
“com/oncotarget metastasis-free survival in breast cancer [20].”
Disordered signaling governing ferroportin transcription favors breast cancer growth
Chen, Y., Zhang, S., Wang, X., Guo, W., Wang, L., Zhang, D., Yuan, L., Zhang, Z., Xu, Y., & Liu, S. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.11.002 · Cited by 54
Functional proteomics outlines the complexity of breast cancer molecular subtypes
Gámez‐Pozo, A., Trilla‐Fuertes, L., Berges‐Soria, J., Selevsek, N., López‐Vacas, R., Díaz‐Almirón, M., Nanni, P., Arevalillo, J. M., Navarro, H., Grossmann, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-10493-w · Cited by 53
Iron overload and altered iron metabolism in ovarian cancer
Rockfield, S., Raffel, J., Mehta, R., Rehman, N., & Nanjundan, M. (2017) · Biological Chemistry · doi:10.1515/hsz-2016-0336 · Cited by 54
“, 2005) and changes in iron metabolism are a property of tumors (Miller et al., 2011).”
InfluentialChen, C., Wang, S., & Liu, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194952 · Cited by 49
Iron metabolism, ferroptosis, and lncRNA in cancer: knowns and unknowns
Qu, L., He, X., Tang, Q., Xiao, F., Liu, J., & Lin, A. (2022) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2200194 · Cited by 48
Zhang, W., Yao, W., Yan, Q., Ma, F., Shi, X., Zhao, Y., Peng, Y., Wang, J., & Jiang, B. (2013) · Oncology Reports · doi:10.3892/or.2013.2828 · Cited by 45
Thielmann, C. M., da Silva, M. C., Muley, T., Meister, M. A., Herpel, E., & Muckenthaler, M. U. (2019) · Scientific Reports · doi:10.1038/s41598-019-47833-x · Cited by 44
Rehwald, C., Schnetz, M., Urbschat, A., Mertens, C., Meier, J. K., Bauer, R., Baer, P. C., Winslow, S., Roos, F. C., Zwicker, K., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0655-7 · Cited by 44
Iron-Bound Lipocalin-2 Protects Renal Cell Carcinoma from Ferroptosis
Meier, J. K., Schnetz, M., Beck, S., Schmid, T., Dominguez, M., Kalinovic, S., Daiber, A., Brüne, B., & Jung, M. (2021) · Metabolites · doi:10.3390/metabo11050329 · Cited by 45
“Tumor cells adopt an iron-retaining phenotype [18], thereby maintaining a delicate balance of metabolically required iron and cytotoxic effects of excessive iron.”
BackgroundFerroptosis‐Enhanced Cancer Immunity by a Ferrocene‐Appended Iridium(III) Diphosphine Complex
Wang, W., Ling, Y., Zhong, Y., Li, Z., Tan, C., & Mao, Z. (2021) · Angewandte Chemie · doi:10.1002/ange.202115247 · Cited by 42
Barra, J., Crosbourne, I., Roberge, C. L., Ramos, R. B., Warren, J., Matteson, K., Wang, L., Jourd’heuil, F. L., Borisov, S. M., Bresnahan, E. R., et al. (2024) · Oncogene · doi:10.1038/s41388-023-02933-x · Cited by 48
“Fluorescence dequenching of RDA and mean intensity of FerroOrange, MitoSOX red, or TMRM was analyzed in 40 cells per condition using ImageJ software (NIH).”
Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications
Rao, V. A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4877 · Cited by 37
“For example, an iron regulatory gene signature has been suggested to predict outcomes in breast cancer patients (170).”
BackgroundBalachandran, V. P., Arora, A., Gönen, M., Ito, H., Turcotte, S., Shia, J., Viale, A. J., Snoeren, N., van Hooff, S. R., Rinkes, I. H. M. B., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1071 · Cited by 38
“successful identification of prognostic gene signatures using the SPCA method(23-25), we chose to employ this mathematical approach to gene selection.”
Spangler, B., Fontaine, S. D., Shi, Y. H., Sambucetti, L. C., Mattis, A. N., Hann, B. C., Wells, J. A., & Renslo, A. R. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01470 · Cited by 39
DCYTB is a predictor of outcome in breast cancer that functions via iron-independent mechanisms
Lemler, D. J., Lynch, M. L., Tesfay, L., Deng, Z., Paul, B. T., Wang, X., Hegde, P., Manz, D. H., Torti, S. V., & Torti, F. M. (2017) · Breast Cancer Research · doi:10.1186/s13058-017-0814-9 · Cited by 38
“Discussion DCYTB was identified as one of 16 genes comprising an iron regulatory gene signature (IRGS) that is predictive of breast cancer patient survival [32].”
BackgroundMethodInfluentialMulens‐Arias, V., Rojas, J. M., & Barber, D. F. (2020) · Nanomaterials · doi:10.3390/nano10050837 · Cited by 39
NGAL as a Potential Target in Tumor Microenvironment
Crescenzi, E., Leonardi, A., & Pacifico, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212333 · Cited by 34
“Consequently, iron-dependent genes like transferrin receptor and ferritin are massively up-regulated in neoplastic cells so much so that their altered expression represents a marker of poor prognosis for patients suffering from different tumors [68], such as colon carcinoma [69], breast cancer [70], and oral squamous…”
BackgroundTargeting 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. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-0218 · Cited by 35
Elevation in Inflammatory Serum Biomarkers Predicts Response to Trastuzumab-Containing Therapy
Alkhateeb, A. A., Leitzel, K., Ali, S. M., Campbell‐Baird, C., Evans, M., Fuchs, E., Köstler, W. J., Lipton, A., & Connor, J. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051379 · Cited by 35
“Recently, the ferritin receptor, Scara5, has been included in a prognostic gene panel for breast cancer indicating that the capability of cancer cells to uptake ferritin may confer a survival or proliferative advantage [34].”
BackgroundTsunedomi, R., Iizuka, N., Yoshimura, K., Iida, M., Tsutsui, M., HASHIMOTO, N., Kanekiyo, S., Sakamoto, K., Tamesa, T., & Oka, M. (2013) · International Journal of Oncology · doi:10.3892/ijo.2013.1854 · Cited by 34
“It has been suggested that changes in iron regulation characterize the malignant state and the iron regulatory gene signature was associated with breast cancer prognosis (46).”
BackgroundMcCarty, M. F., & Contreras, F. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00249 · Cited by 34
“Conversely, genetic expression patterns that predict efficient iron uptake (high transferrin receptor, low hereditary hemochromatosis), and low capacity for iron export (low transportin, high hepcidin) are associated with greater risk of recurrence and decreased survival in breast cancer patients (71, 75).”
BackgroundShotgun proteomics of archival triple‐negative breast cancer samples
Gámez‐Pozo, A., Ferrer, N. I., Ciruelos, E., López‐Vacas, R., Garcı́a, F., Espinosa, E., & Vara, J. Á. F. (2013) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201200048 · Cited by 34
“We used previously published array expression data from two previous works [27, 28].”
MethodChen, Y., Zhang, F., Du, Z., Xie, J., Xia, L., Hou, X., Hao, E., & Deng, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.727130 · Cited by 35
“Studies have shown significantly increased ferritin in tumor patients with inhibited iron efflux (31).”
BackgroundPhenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis
Yang, Y., Lu, Y., Zhang, C., Guo, Q., Zhang, W., Wang, T., Xia, Z., Liu, J., Cheng, X., Xi, T., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04384-1 · Cited by 34
“Notably, the decrease of iron output-related genes and the increase of iron input-related genes represent a better prognosis in breast cancer patients [21], and the CSC marker CD44 can mediate iron endocytosis in CSCs [22].”
BackgroundFerrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS -driven tumors
Jiang, H., Muir, R. K., Gonciarz, R. L., Olshen, A. B., Yeh, I., Hann, B. C., Zhao, N., Wang, Y.-H., Behr, S. C., Korkola, J. E., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20210739 · Cited by 33
“Consistent with previous observations in breast cancer (Miller et al., 2011; Pinnix et al., 2010), prostate cancer (Tesfay et al., 2015), and glioblastoma (Schonberg et al., 2015), we have now confirmed an altered iron metabolic state in PDA characterized by the elevation of cytosolic labile…”
Trace Elements and Healthcare: A Bioinformatics Perspective
Zhang, Y. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-5717-5_4 · Cited by 34
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“found that an iron anti-import phenotype with concomitant low TfR1 and high HFE was significantly associated with favorable prognosis of BC patients [21].”
Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators
Akam, E. A., Chang, T. M., Astashkin, A. V., & Tomat, E. (2014) · Metallomics · doi:10.1039/c4mt00153b · Cited by 32
Matthew-Onabanjo, A. N., Janusis, J., Mercado-Matos, J., Carlisle, A. E., Kim, D., Levine, F. A., Cruz‐Gordillo, P., Richards, R., Lee, M. J., & Shaw, L. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1555 · Cited by 34
“In breast cancer, iron levels are increased when compared with normal breast tissue and an iron-regulatory gene signature is prognostic for patient outcome (58).”
BackgroundIron participated in breast cancer chemoresistance by reinforcing IL-6 paracrine loop
Li, J., He, K., Liu, P., & Xu, L. X. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.05.064 · Cited by 32
Gámez‐Pozo, A., Trilla‐Fuertes, L., Prado-Vázquez, G., Chiva, C., López‐Vacas, R., Nanni, P., Berges‐Soria, J., Grossmann, J., Díaz‐Almirón, M., Ciruelos, E., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0178296 · Cited by 32
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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