Local iron homeostasis in the breast ductal carcinoma microenvironment
Open accessAbstract
BACKGROUND: While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. METHODS: Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. RESULTS: We confirm previous results by showing that breast cancer epithelial cells present an 'iron-utilization phenotype' with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an 'iron-donor' phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. CONCLUSIONS: The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context.
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Enhanced hepcidin expression in breast cancer patients points to an autocrine/paracrine regulatory mechanism in order to reduce control local tumor iron efflux.
“Enhanced hepcidin expression in breast cancer patients points to an autocrine/paracrine regulatory mechanism in order to reduce control local tumor iron efflux [50].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [50]
Anti-inflammatory macrophages and lymphocytes show an iron release phenotype, donating and distributing iron within the tumor microenvironment.
“In contrast to the iron sequestration phenotype of inflammatory macrophages induced by pro-inflammatory cytokines and danger-associated molecular patterns (DAMPs), anti-inflammatory macrophages and lymphocytes show an iron release phenotype, donating and distributing iron within the tumor microenvironment.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [50]
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- Authors
- Marques, O., Porto, G., Rêma, A., Faria, F., Cruz Paula, A., Gomez-Lazaro, M., Silva, P., Martins da Silva, B., & Lopes, C.
- Affiliations
- Universidade do Porto (PT)
- Corresponding author
- Marques, Oriana
- Venue
- BMC Cancer
- Published
- 2016-03-05
- Volume
- 16
- Issue
- 1
- Pages
- 187-187
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC4779214
- OpenAlex
- W2290972191
- Cited by
- 90
- References
- 58
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 17 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 5 · 2015: 1
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- Fundação para a Ciência e a Tecnologia (SFRH/BD/2011/78184, SFRH/BD/74307/2010)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- iron homeostasis, breast ductal carcinoma, tumor microenvironment, ferroportin 1, hepcidin, transferrin receptor 1, ferritin, tumor-associated macrophages, lymphocytes, axillary lymph node metastasis, iron accumulation, tumor stroma, imaging flow cytometry, hormone receptor status, tumor size, prognosis
- MeSH terms
- Ferroportin, Breast Neoplasms, Female, Flow Cytometry, Homeostasis, Humans, Immunohistochemistry, Iron, Lymph Nodes, Receptors, Transferrin, Biomarkers, Antigens, CD, Gene Expression, Carcinoma, Ductal, Breast, Cation Transport Proteins, Tumor Burden, Tumor Microenvironment, Hepcidins
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