Iron biology, menopause, and the breast cancer puzzle

Background and biological mechanisms

Breast cancer is the most common cancer in women (1), yet the role of iron in breast carcinogenesis remains uncertain (2). Iron deficiency is one of the most common nutrient deficiencies globally (3), particularly among pre-menopausal women (4). Iron is complex because the absorption, and possibly health effects, vary by source and intake level. Iron’s cancer-relevant biology is bidirectional; iron imbalances can occur in two ways, overload or deficiency, both severely impacting normal biological processes (5).

Iron overload has been shown to induce oxidative DNA damage (6) and lipid peroxidation, leading to mitochondrial damage, changes that are implicated in mutagenesis and tumor progression (7,8). Conversely, iron deficiency can impair DNA repair (9) and reduce antitumor immune surveillance, potentially jeopardizing the immune system’s ability to detect and eliminate cancer cells (10), creating conditions in which tumor progression is facilitated. Layered onto these classical mechanisms, the newly characterized iron-dependent form of cell death, known as ferroptosis, appears to play a dual role in cancer biology. In several solid tumors, it can act as a tumor suppressor and inhibit the invasion and metastasis, yet ferroptosis may also contribute to carcinogenesis in certain conditions (11). The tumor microenvironment adds further complexity, because altered iron handling by macrophages can foster breast tumor progression through inflammatory and metabolic signaling (12).

Biomarkers and prior evidence

Clinically, circulating biomarkers provide a window into systemic iron status. While serum iron is a relatively nonspecific marker, ferritin and transferrin saturation (TSAT, the proportion of transferrin bound to iron) are more informative indicators of body and tissue iron reserves (13,14). Epidemiologic findings remain heterogeneous and World Cancer Research Fund (WCRF) in 2018 classified iron as being with “limited – no conclusion” related to risk of breast cancer, highlighting that the current evidence base is poor (2). A meta-analysis published in 2019 of 11 prospective studies reported higher breast cancer risk in relation to heme iron intake and serum/plasma iron concentrations, but no association for ferritin, TSAT, or total iron-binding capacity (TIBC) (15). Since the WCRF evaluation and the meta-analysis, iron biomarkers in relation to breast cancer risk have been investigated in a case-cohort design in the Sister Study including 3,011 incident breast cancer cases. Serum iron, ferritin, and TSAT showed no overall association with breast cancer; however, in post hoc stratified analyses premenopausal women in the lowest ferritin quartile had a lower risk than those in the higher quartiles [hazard ratio (HR) 0.73, 95% confidence interval (CI): 0.54–0.99] (16). This finding rests on a post hoc, exploratory contrast [quartile (Q) 1 vs. Q2–4], which limits interpretability. Coarse categorization of a continuous biomarker discards information, relies on arbitrary cutpoints, can mask non-linear dose-response. Overall, the current evidence is thus very limited, and further research is therefore warranted to better understand the complex relationship between physiological iron and cancer development. The current large-scale Korean cohort (17) adds crucial nuances.

Korean cohort findings

Kim et al. investigated the association between iron-biomarkers and the risk of breast cancer in 140,747 Korean women screened for breast cancer (17). Women were excluded for several reasons, including but not limited to acute inflammation (to avoid acute-phase distortion of iron markers), anemia, and use of iron-containing dietary supplements. The markers were measured in fasting blood samples and included serum ferritin, iron and TIBC. Based on TIBC and serum iron, TSAT was estimated. These represent markers of iron stores (ferritin) and functional iron (TSAT). During a median follow-up of 6.7 years, 1,437 were diagnosed with breast cancer. No association was found between iron biomarkers and the rate of breast cancer among postmenopausal women, however, a tendency toward a higher breast cancer risk with high iron concentrations was observed. For premenopausal women, higher concentration of serum ferritin was associated with a lower risk of breast cancer. When comparing those with a concentration in the highest quartile (≥67.9 ng/mL) to those in the lowest (<22 ng/mL) the adjusted HR was 0.76 (95% CI: 0.64–0.89). Splines of the association were also presented as supplementary material, and indicated a sign of dose-response relationship. Additionally, models adjusting for a large number of reproductive factors found a similar relationship. However, when stratifying by body mass index (BMI), the association was more pronounced in premenopausal women with obesity.

This pattern is biologically coherent and mechanistically plausible: higher ferritin is associated with lower breast cancer risk among premenopausal women, with consistent signals for both invasive cancer and ductal carcinoma in situ, and a stronger inverse relationship in those with obesity. In contrast, no protective association was observed postmenopausally, and iron and TSAT trended positively with risk in that group. This makes sense when we recall that ferritin is a dual-purpose protein integrating iron storage and inflammation, two axes that shift substantially with the menopausal transition.

Obesity as an amplifier of ferritin’s inverse association premenopause

The study reports a stronger inverse association in obese premenopausal women. At first glance, that may appear counterintuitive because obesity often promotes low-grade inflammation and higher hepcidin, both of which often raises ferritin. A coherent way to read this is to separate “iron availability” from “iron storage”. In the premenopausal state, higher ferritin can still reflect effective sequestration of labile iron. Adipose-induced inflammation and hepcidin levels may reduce iron efflux into the breast microenvironment. If menstrual cycling and the premenopausal hormonal milieu are simultaneously in play, the net effect can be fewer sublethal oxidative injuries in breast tissue, not more. If iron is more effectively buffered in the breast microenvironment, then, despite an inflammatory background, there may be fewer sublethal oxidative hits. A second layer may involve lipid peroxidation and ferroptosis, an iron-dependent cell death program that clears damaged cells once a trigger threshold is reached. Obesity increases the lipids that can be oxidized. If iron sequestration is concurrently enhanced, the system may have fewer oxidative hits and a higher chance that damaged cells are removed by ferroptosis instead of surviving with DNA damage. This could help explain the stronger inverse pattern in this subgroup. These ideas can be tested by tracking, over time, oxidized lipids, ferroptosis markers, and iron-handling proteins.

A necessary caution: residual confounding by adiposity

Importantly, even a coherent biological rationale does not rule out bias. Ferritin is higher in women with obesity, and obesity also protects against premenopausal breast cancer (2). Although Kim et al. adjusted for BMI—and conducted an effect-modification analysis showing a stronger inverse association at higher BMI—BMI is an imperfect measure of adiposity, and in this study, it was modeled in categories rather than continuously, which increases the potential for residual confounding. Thus, the finding could still act as a proxy for adiposity-linked ovulatory patterns and altered menstrual bleeding patterns (18), which may be related to lower premenopausal breast cancer risk.

Why the postmenopausal null is informative rather than disappointing

After menopause, the ground shifts: Monthly iron loss stops, hepcidin rises, and adiposity often increases. In this setting, a higher ferritin level is more likely to reflect systemic inflammation and metabolic dysfunction like insulin resistance and hepatic steatosis as much as, or more than, iron storage. That shift can weaken any inverse association mediated by iron sequestration. The study’s null finding in postmenopausal women is therefore not a disappointment but may be a clue that ferritin’s “meaning” changes with physiological state.

The study’s small positive trends for serum iron and TSAT in postmenopausal women, especially in time-updated analyses, may also make biological sense because iron stores rise after periods stop. They also highlight a measurement issue: a single baseline measure cannot capture changes across the menopausal transition, suggesting repeated measurements, finer stratification by time since menopause, and consideration of hormone therapy are needed.

Hormonal-immune context, intake and absorption shape biomarkers

The editorial takeaway is not that “more iron is better” before menopause. Rather, in premenopausal women, a higher ferritin level more often reflects adequate storage and tighter control of the labile iron pool that matters for carcinogenesis. The same ferritin number, read in a postmenopausal body, may be telling you about inflammation or metabolic dysfunction instead.

Together, the biology and the new cohort evidence sharpen an important hypothesis: the impact of iron on breast carcinogenesis is context dependent, shaped by hormonal state and immune tone. Altogether, the study suggests inverse associations in premenopausal women and null to positive trends in postmenopausal women. Because women with anemia and users of iron-containing supplements were excluded, the cohort reflects a generally healthy, iron-supplement-naïve population.

Iron intake and its biological impact vary by source and meal context. Heme iron from meat is generally more bioavailable than non-heme iron from plant foods, with absorption modulated by enhancers such as vitamin C and inhibitors such as phytates and calcium (19,20). Although Kim et al. did not assess dietary sources, these differences matter for interpreting iron biomarkers in relation to breast cancer, and they underscore the need for future cohorts to integrate dietary sources, enhancers/inhibitors of absorption, supplement use, menopause status and other factors (Figure 1).

Figure 1 Conceptual framework for iron-breast cancer research incorporating iron biomarkers, sources (diet, dietary enhancers & inhibitors), and host biology (genetics, sex, inflammation, body composition, menopausal status) in iron–breast cancer research. Examples are illustrative, not exhaustive, and further factors could be incorporated.

Public health guidance and research needs

From a public health perspective, based on Kim et al., the evidence is not yet sufficient to change public health recommendations, and findings remain mixed: while Kim et al. report an inverse association for ferritin in premenopausal women, a prior case-cohort study found the opposite (16), and a meta-analysis did not identify a significant overall association (15). Our updated, targeted literature check did not reveal additional large, high-quality prospective studies on iron status or dietary iron and breast cancer risk that would materially change the conclusions of the WCRF report (2) and the 2019 meta-analysis (15), reinforcing the current classification of iron as “limited – no conclusion” in relation to breast cancer risk.

Iron is complex in sources, absorption, and biological effects, and high levels can be harmful, particularly with heme-rich or supplemental forms (21). Policy and clinical guidance will require more detailed data on dietary sources and meal context, as well as genetic variation influencing iron metabolism. Until we have integrated cohort and mechanistic data across diet, genetics, and the menopausal transition, iron guidance should remain conservative: correct deficiency when present, avoid high-dose supplementation without indication, and recognize that the same ferritin level may carry different implications before and after menopause. In the context of more sustainable diets, robust evidence on how to maintain iron requirements with lower meat intake is urgently needed, as emphasized in the recently published update of the EAT-Lancet Commission (22).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article has undergone external peer review.

Peer Review File: Available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0010/prf

Funding: This work was supported by grant from Plantefonden (The Danish Plant-Based Food Grant, jr. nr. 36016-25-0334, to C.K.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0010/coif). C.K. received grant from Plantefonden [The Danish Plant-Based Food Grant, (jr. nr. 36016-25-0334)]. C.K. serves as a member of the Scientific Board of the Danish Cancer Research Foundation (Dansk Kræftforskningsfond), a private, researcher-led foundation founded in 1991 that supports young researchers and new, independent research projects across all cancer types to improve prevention, treatment, and rehabilitation; this is an unpaid position. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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