Iron intake, oxidative stress‐related genes and breast cancer risk

Abstract

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/ progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case-control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER-/PR-breast cancer risk (all p trend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR >18 vs. 0 mg/day = 0.68, 95% CI: 0.51-0.91), and dietary heme iron was associated with an increased risk, particularly the ER-/PR-subtype (OR highest vs. lowest quintile = 1.69, 95% CI: 1.16-2.47; p trend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (p interaction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.

Pre-Clinical Insights into the Iron and Breast Cancer Hypothesis

“…Consistent with other preclinical reports, effects were modest and not statistically significant [ 47 ]. More importantly, the data were consistent with three population studies published between 2019 and 2021 [ 6 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Specifically, we evaluated the data ( Table 5 ) in a manner that paralleled the common approach in epidemiology, contrasting low versus high iron status, i.e., by comparing groups 1–3 vs. 4–7: the cancer incidence was 63.3 vs. 70.0 (RR = 1.10 (0.95, 1.20; p = 0.098)).…”

“…Recently reported results from population studies, systematic reviews, and meta-analyses revealed no relationship between iron status and breast cancer, a weak positive association, or a small protective effect of low iron status [ 6 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. However, in most of those studies, the authors concluded that further investigation was merited.…”

“…The prevailing issues underlying those investigations included the impact of iron deficiency in limiting processes related to tumor development and the effects of excess iron-induced oxidative stress on the carcinogenic process. Papers published between 2017 and 2021 [ 6 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] indicated that this cycle of interest is once again repeating. The prevailing hypotheses include not only those that were prominent in the 2008–2013 timeframe but also those that are centered on iron metabolism as regulated by hepcidin, with extension to how the gut microbiome and immune system might be involved in effect mediation.…”

Targeting ferroptosis, the achilles’ heel of breast cancer: A review

“…A European randomized controlled study showed there was a positive association between serum transferrin level and the incidence of ER- breast cancer ( Hou et al, 2021 ). A Canadian cohort study showed that dietary iron supplementation was associated with a low risk of breast cancer, and heme iron was positively related with the risk of the ER and or PR positive breast cancer subtypes in postmenopausal women ( Chang et al, 2020 ). High ferroportin and hepcidin expression play a protective role in patients with breast cancer ( Pinnix et al, 2010 ).…”

DNA Repair/Oxidative Stress Genes and Pain in Cancer Survivors on Aromatase Inhibitors

“…Oxidative stress may be associated with the estrogen/progesterone receptor status of the tumor [10,17] and may persist for up to 6 months post tumor removal in women with breast cancer [18]. DNA repair enzymes help maintain stability in the genome, and malfunctions in DNA repair pathways are linked to the progression and development of breast cancer [19].…”