- Open Access
Environmental impact on carcinogenesis under BRCA1 haploinsufficiency
Genes and Environment volume 45, Article number: 2 (2023)
Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain “iron addiction with ferroptosis-resistance” where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy.
Cancer is the leading cause of human mortality in Japan since 1981 (https://ganjoho.jp/public/qa_links/report/statistics/2022_en.html). Although numerous novel therapies, such as immune checkpoint inhibitors  and chimeric antigen receptor T-cell therapy , have been developed and applied in clinics recently, the number of deaths from cancer is still increasing worldwide (https://www.who.int/news-room/fact-sheets/detail/cancer). It is time to consider the strategies for cancer prevention more seriously and comprehensively to decrease the burden to the society.
We have been proposing a hypothesis that cancer can be the side effects of long-time use of iron and oxygen  if we can eliminate the established risks, including physical, chemical and biological carcinogens (https://www.who.int/news-room/fact-sheets/detail/cancer) and that carcinogenesis is generally a process to obtain “iron addiction with ferroptosis-resistance” . The proof of concept for this hypothesis is that iron is indispensable for cell proliferation to replicate DNA  and that Fe(II) is a catalyst for the Fenton reaction, which generates the most damaging and mutagenic chemical species, hydroxyl radical . This is further based on our own observation and observation by other investigators that 1) excess iron in various human pathology is associated with higher risk for carcinogenesis [7,8,9]; 2) iron reduction by phlebotomy decreases the cancer risk and mortality in a human intervention study ; 3) repeated iron-catalyzed Fenton reaction causes aggressive cancer that is similar to human counterparts not only in macroscopic/microscopic morphology but also in genetic alterations [11, 12]. These animal models include ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis [12,13,14,15] and asbestos-induced mesothelial carcinogenesis in rats [16,17,18,19]; 4) especially in the latter case, iron removal by iron chelating agent  or phlebotomy  can prevent mesothelial carcinogenesis to some extent. More detailed review on these topics are found elsewhere [9, 12, 22]. At first, we here describe the recent advances in iron metabolism in mammals, including the concept of ferroptosis.
Recent advances in iron metabolism
Iron is the most abundant heavy metal in our body and is indispensable for all the lives on earth [7, 23, 24]. Iron basically works in two ways in higher mammals: 1) persistent electron transfer via redox cycling and 2) temporary oxygen storage as heme in hemoglobin, myoglobin, neuroglobin and cytoglobin. Indeed, ~ 60% of iron is in hemoglobin in humans. Because iron is thus important, our body is deficient of any active mechanism to discharge iron to outside our body .
Serum iron-transporting protein, transferrin, has been recognized since 1946  and transferrin receptor 1 was identified in 1981 . Iron storage protein ferritin was cloned in 1986 . However, it took some extra time for membrane iron transporters and iron chaperones to be established [28, 29]. Of note, Fe(III) is insoluble at neutral pH and used for extracellular transport and intracellular storage (Fig. 1). In contrast, Fe(II) is soluble and used for transport across the membrane and intracellular transport. Labile iron is a concept indicating cytosolic mobile free iron , but some ambiguity still remains in that labile iron includes catalytic Fe(II), chaperoned Fe(II) by poly(rC) binding protein 1/2 (PCBP1/2) [31, 32] and dinitrosyl-diglutathionyl iron complex (DNDGIC) . Figure 2 shows the current summary of iron metabolism.
A recent new finding in iron metabolism is that our cells use exosomes for the monopoly of iron inside ourselves . The importance of iron for survival is the same for other microorganisms, such as bacteria, fungi and parasites. Those infectious agents try to steal iron from our cells. They use many different molecules, including siderophores . Interestingly, one of the siderophores of a bacterium, desferrioxiamine, is used as an iron-chelating agent for medical use . We recently found that a characteristic membrane surface molecule on exosome, CD63, is under the regulation of iron-responsive element/iron-regulatory protein (IRE/IRP) system . This posttranscriptional regulatory system is specific for iron metabolism and IRE sequence is observed either in the 5’ or 3’ portion of mRNA of iron metabolism-associated genes. This is a system for iron deficiency (Fig. 2), considering the era of hunger . Transferrin receptor 1 (Tfr1) mRNA has 5 IREs in the 3’ portions, thus increasing the lifetime of this message to increase the amounts of the Tfr1 protein. Conversely, translation of iron storage protein Fth1/Ftl is blocked for translation when the cell is iron-deficient. In the case of CD63, IRE sequence is present at the 5’ portion. If the cells harbor ample amounts of iron, this will be deblocked and exosomes with iron-loaded ferritin is generated through nuclear receptor activator 4 (NCOA4) and secreted toward the other cells of the same individual. Indeed, this is a safe strategy to transfer surplus iron to neighbor iron-deficient cells. Here we would like to stress that this IRE sequence in CD63 is present only in higher primates and is not present in mice or rats, which are used for experiments. However, this system is abused in asbestos-induced mesothelial carcinogenesis [22, 38, 39].
There are only two types of cell death classified by light microscopy, necrosis and apoptosis. However, starting from the 2000’s, many cell death modes were proposed, defined by the specific signaling pathways. These include ferroptosis (Fig. 3), catalytic Fe(II)-regulated necrosis accompanied by lipid peroxidation [40, 41]. Ferroptosis just celebrated its 10th birthday in 2022, and this cell mode became popular evidenced by the exponentially increasing number of papers studying ferroptosis .
We have been working on iron-induced carcinogenesis for decades. Among them, repeated intraperitoneal injections of ferric nitrilotriacetate (Fe-NTA) induces renal cell carcinoma (RCC) in a high incidence (60 ~ 90%) in male rats [9, 12]. In this model, renal tubular necrosis is observed as early as 30 min in the proximal tubular cells with various lipid peroxidation products [43,44,45,46], which are the observation of our own in the 1980’s and 1990’s. When we first recognized the word ferroptosis in 2014, we immediately accepted it, based on our experience of this oxidative renal tubular damage. In the Fe-NTA-induced renal carcinogenesis model, renal tubular cells obtain ferroptosis-resistance in a few weeks after continued iron-catalyzed oxidative stress [12, 47, 48]. We have been proposing a hypothesis that carcinogenesis is a process to acquire ferroptosis-resistance under iron addiction via somatic mutation(s) . Iron is an essential cofactor for ribonucleotide reductase for DNA synthesis and replication [49, 50], which is indispensable for proliferating cancer cells.
Accordingly, cancer cells harbor higher amounts of catalytic Fe(II) in the cytosol in comparison to the non-tumorous cells [51, 52]. This high amounts of catalytic Fe(II) is useful for DNA replication but also causes persistent oxidative stress to the cancer cells . Thus, cancer cells are prepared to counteract this oxidative stress, for example, via the activation of Nrf2 transcription factor, a master regulator of antioxidative genes [54, 55]. Ferroptosis may be interpreted as relative predominance of iron over sulfur (sulfhydryls) by stimuli, which is modulated by the amounts of polyunsaturated fatty acids (PUFAs), mainly as phospholipids, in the cellular membrane (Fig. 3). This is indeed the Achilles’ heels of cancer cells and numerous ferroptosis inducers are currently under investigation for cancer therapy [3, 5, 56].
Alternatively, we recently found physiological ferroptosis. We selected a mouse monoclonal antibody for 4-hydroxy-2-nonenal (HNE)-modified proteins, HNEJ-1 clone, to detect ferroptotic cells in formalin-fixed paraffin-embedded specimens [57, 58]. Our present conclusion is that ferroptotic event occurs in nucleated red blood cells at E13.5 and aging cells of various organs in rats . Thus, it is not strange to find ferroptosis in neuronal cells in various neurogenerative diseases [60,61,62]. Here researchers are trying to stop ferroptosis in the dying neuronal cells by developing agents to prevent ferroptosis. In summary, ferroptosis is now an optimal target for the development of new drugs both for induction and prevention.
Current understanding is that cancer is a disease of the genome . Thus far, we suggested that iron and oxygen can be the major mutagens in the long human lifetime of more than 80 years [3, 64]. Other than iron and oxygen, there are a plethora of mutagenic agents exposed to humans via skin, respiratory tract or gastrointestinal tract, which are both natural and industrial (https://monographs.iarc.who.int/agents-classified-by-the-iarc/). On the other hand, genetic susceptibility of each individual is as important as mutagens because there would be no carcinogenesis if the prevention and repair processes are perfect. Various familial cancer syndromes have been recognized from long time ago . Since 1990’s, tumor suppressor genes were identified and cloned one by one . These were the genes for the repair of various damage to genomic DNA or the genes to cause cell death with defined levels of biological/chemical/physical stimulus or damage. One of the most socially recognized tumor suppressor genes is BRCA1 due to the famous Hollywood actress, Angelina Jolie, known as the Angelina effect [66, 67].
Here according to a recent report on the Japanese population, the target organs for carcinogenesis of BRCA1 mutants include female breast (odds ratio [OR], 16.1; p = 3.50 × 10–11) and ovary (OR, 75.6; p = 2.26 × 10–22) , which are critical for reproduction as the nutrient source of for the next generation and the reserve of oocytes, respectively. The present guideline still recommends prophylactic mastectomy  and oophorectomy  when necessary, which has been sensational to the general public. A higher risk for biliary tract cancer (OR, 17.4; p = 2.96 × 10–7), pancreatic cancer (OR, 12.6; p = 4.67 × 10–5) and gastric cancer (OR, 5.2; p = 3.40 × 10–6) is also noted recently for BRCA1 mutants . Considering the characteristics of target organs in BRCA1-associated carcinogenesis, we hypothesized that iron-associated oxidative stress may be in common as a promotional factor, especially for breast and ovary. This is based on the fact that both organs are deeply associated with iron metabolism including lactoferrin secretion in milk [71, 72] and ovulation. Ovarian endometriosis is closely associated with ovarian carcinoma through iron-mediated oxidative stress [73,74,75,76]. If so, some other preventive strategies may be possible.
Species difference in animal experiment
BRCA1 tumor suppressor gene was cloned in 1994 by Miki et al. . Thereafter, hundreds of trials were performed to generate a feasible murine model of human BRCA1 mutants. However, this was not successful in that heterozygous knockout of BRCA1 alone showed no phenotype in carcinogenesis whereas homozygous knockout was embryonic lethal . Many conditional knockout mice model was produced, but the results were negative. If the heterozygous knockout mice were crossed with TP53( ±) mice, the mice showed susceptibility to basal-like breast cancer .
However, it was surprising that rat Brca1 mutant model (L63X/ +) shows the phenotype. This model was developed by Imaoka and Mashimo et al. in 2022 in Japan . We believe that this is a species difference and that Rattus norvegicus is significantly closer to Homo sapiens in comparison to Mus musculus. We thus far observed similar phenomena in Fe-NTA-induced renal carcinogenesis. Whereas renal carcinogenesis is observed in mice and rats, phenotypes are quite different (Table 1), which is much milder in mice in comparison to rats .
BRCA1 and ferroptosis-resistance
We have recently applied Fe-NTA renal carcinogenesis model to male Brca1(L63X/ +) rats to evaluate whether iron-catalyzed oxidative stress  is important for Brca1 mutant carcinogenesis . The incidence of renal carcinogenesis was not changed between the Brca1 mutant and the wild-type. However, the carcinogenesis was significantly promoted in the Brca1 mutants by 3 months on average in comparison to the wild-type, which is a marked difference considering the average life time rats of ~ 3 y. This result indicates that iron-catalyzed oxidative stress is a promoting factor of carcinogenesis for Brca1 mutants.
Furthermore, we found that renal cell carcinomas (RCCs) in Brca1 mutants show more genomic alterations, including c-Myc amplification , which is indeed frequently observed in the breast carcinoma of human BRCA1 mutants  and is a risk for poor prognosis [88, 89]. Here c-Myc amplification was often extrachromosomal. These results suggest that iron removal or avoidance of oxidative stress in the target organs could be an effective measure to prevent carcinogenesis in BRCA1 mutants.
We then undertook to understand the molecular mechanism why iron-catalyzed oxidative stress promotes renal carcinogenesis. We have performed expression microarray analysis in the subacute phase of 3 weeks during the renal carcinogenesis and found that higher mitochondrial damage is a key phenomenon . Electron microscopical analysis revealed that even the untreated control kidney showed smaller and deformed mitochondria in the renal tubular cells of Brca1 mutants. Since mitochondria play a central role in iron metabolism producing heme, it is plausible that mitochondrial damage alters iron metabolism in the entire cell, which produced a niche for carcinogenesis under mutagenic environment with Fe(III) abundance but with less catalytic Fe(II) at the subacute phase in the Brca1 mutants in comparison to the wild-type. This is the mechanism how iron addiction with ferroptosis-resistance was generated (Fig. 4). We recently obtained similar results on chrysotile-induced malignant mesothelioma by the use of male Brca1(L63X/ +) rats . However, we still need to know the role of Brca1 haploinsufficiency in this mitochondrial damage and the demonstration in human BRCA1 mutant samples would be necessary.
Cancer is basically a disease of the genome, where genome and environment persistently interact each other. We believe that even the long-use of iron and oxygen eventually causes various mutations, which may explain why aging stands as one of the highest risks for cancer. Some of the cancer susceptibility can be explained by the inactivation of tumor suppressor genes. Here this review article focused on how we undertook to find promoting factors in BRCA1 mutants with a recently established rat Brca1(L63X/ +) model. During iron-induced renal carcinogenesis, Brca1 haploinsufficiency allowed more genomic alterations, including amplification of c-Myc. Therefore, environmental factors, such as the control of iron and oxidative stress, may work as a strategy to prevent or delay carcinogenesis in BRCA1 mutants.
Availability of data and materials
Dinitrosyl-diglutathionyl iron complex
Iron-responsive element/iron-regulatory protein
Nuclear receptor activator 4
Poly(rC) binding protein 1/2
Polyunsaturated fatty acids
Renal cell carcinoma
Sharma P, Allison JP. Dissecting the mechanisms of immune checkpoint therapy. Nat Rev Immunol. 2020;20(2):75–6.
Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62.
Toyokuni S, Kong Y, Cheng Z, Sato K, Hayashi S, Ito F, et al. Carcinogenesis as Side Effects of Iron and Oxygen Utilization: From the Unveiled Truth toward Ultimate Bioengineering. Cancers (Basel). 2020;12(11):3320.
Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Free Radic Biol Med. 2017;108:610–26.
Toyokuni S, Yanatori I, Kong Y, Zheng H, Motooka Y, Jiang L. Ferroptosis at the crossroads of infection, aging and cancer. Cancer Sci. 2020;111:2665–71.
Koppenol WH, Hider RH. Iron and redox cycling Do’s and don’ts. Free Radic Biol Med. 2019;133:3–10.
Toyokuni S. Iron-induced carcinogenesis: the role of redox regulation. Free Radic Biol Med. 1996;20:553–66.
Toyokuni S. Iron and thiols as two major players in carcinogenesis: friends or foes? Front Pharmacol. 2014;5:200.
Toyokuni S. The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosisresistance to non-thermal plasma therapy. Pathol Int. 2016;66:245–59.
Zacharski L, Chow B, Howes P, Shamayeva G, Baron J, Dalman R, et al. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: Results from a randomized trial. J Natl Cancer Inst. 2008;100:996–1002.
Akatsuka S, Yamashita Y, Ohara H, Liu YT, Izumiya M, Abe K, et al. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. PLoS ONE. 2012;7(8): e43403.
Toyokuni S, Kong Y, Zheng H, Maeda Y, Motooka Y, Akatsuka S. Iron as spirit of life to share under monopoly. J Clin Biochem Nutr. 2022;71(2):78–88.
Ebina Y, Okada S, Hamazaki S, Ogino F, Li JL, Midorikawa O. Nephrotoxicity and renal cell carcinoma after use of iron- and aluminum- nitrilotriacetate complexes in rats. J Natl Cancer Inst. 1986;76:107–13.
Li JL, Okada S, Hamazaki S, Ebina Y, Midorikawa O. Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate. Cancer Res. 1987;47:1867–9.
Nishiyama Y, Suwa H, Okamoto K, Fukumoto M, Hiai H, Toyokuni S. Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate. Jpn J Cancer Res. 1995;86:1150–8.
Toyokuni S. Mechanisms of asbestos-induced carcinogenesis. Nagoya J Med Sci. 2009;71(1–2):1–10.
Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, et al. Iron overload signature in chrysotile-induced malignant mesothelioma. J Pathol. 2012;228:366–77.
Toyokuni S. Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention. Free Radic Biol Med. 2019;133:206–15.
Toyokuni S, Ito F, Motooka Y. Role of ferroptosis in nanofiber-induced carcinogenesis. Metallomics Res. 2021;1(1):14–21.
Nagai H, Okazaki Y, Chew SH, Misawa N, Yasui H, Toyokuni S. Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelial carcinogenesis in rats. Cancer Prev Res (Phila). 2013;6:1222–30.
Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. Cancer Sci. 2018;109(2):330–9.
Toyokuni S, Kong Y, Zheng H, Mi D, Katabuchi M, Motooka Y, et al. Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles. J Cancer Prev. 2021;26(4):244–9.
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13(5):342–55.
Drakesmith H, Nemeth E, Ganz T. Ironing out Ferroportin. Cell Metab. 2015;22(5):777–87.
Toyokuni S. Role of iron in carcinogenesis: Cancer as a ferrotoxic disease. Cancer Sci. 2009;100(1):9–16.
Sutherland R, Delia D, Schneider C, Newman R, Kemshead J, Greaves M. Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc Natl Acad Sci U S A. 1981;78(7):4515–9.
Hentze MW, Keim S, Papadopoulos P, O’Brien S, Modi W, Drysdale J, et al. Cloning, characterization, expression, and chromosomal localization of a human ferritin heavy-chain gene. Proc Natl Acad Sci U S A. 1986;83(19):7226–30.
Gunshin H, Mackenzie B, Berger U, Gunshin Y, Romero M, Boron W, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388(6641):482–8.
Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt S, Moynihan J, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403(6771):776–81.
Gutteridge J, Rowley D, Halliwell B. Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts Detection of “free” iron in biological systems by using bleomycin-dependent degradation of DNA. Biochem J. 1981;199(1):263–5.
Yanatori I, Richardson DR, Toyokuni S, Kishi F. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. J Biol Chem. 2017;292(32):13205–29.
Yanatori I, Richardson DR, Toyokuni S, Kishi F. The new role of poly (rC)-binding proteins as iron transport chaperones: Proteins that could couple with inter-organelle interactions to safely traffic iron. Biochim Biophys Acta Gen Subj. 2020;1864(11): 129685.
Richardson DR, Lok HC. The nitric oxide-iron interplay in mammalian cells: transport and storage of dinitrosyl iron complexes. Biochim Biophys Acta. 2008;1780(4):638–51.
Yanatori I, Richardson DR, Dhekne HS, Toyokuni S, Kishi F. CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Blood. 2021;138(16):1490–503.
Winkelmann G. Microbial siderophore-mediated transport. Biochem Soc Trans. 2002;30(4):691–6.
Codd R, Richardson-Sanchez T, Telfer TJ, Gotsbacher MP. Advances in the Chemical Biology of Desferrioxamine B. ACS Chem Biol. 2018;13(1):11–25.
Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197–213.
Ito F, Yanatori I, Maeda Y, Nimura K, Ito S, Hirayama T, et al. Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and beta-catenin induction in mesothelium. Redox Biol. 2020;36: 101616.
Ito F, Kato K, Yanatori I, Murohara T, Toyokuni S. Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin. Redox Biol. 2021;47: 102174.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171(2):273–85.
Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185(14):2401–21.
Hamazaki S, Okada S, Ebina Y, Midorikawa O. Acute renal failure and glucosuria induced by ferric nitrilotriacetate in rats. Toxicol Appl Pharmacol. 1985;77:267–74.
Toyokuni S, Uchida K, Okamoto K, Hattori-Nakakuki Y, Hiai H, Stadtman ER. Formation of 4-hydroxy-2-nonenal-modified proteins in the renal proximal tubules of rats treated with a renal carcinogen, ferric nitrilotriacetate. Proc Natl Acad Sci USA. 1994;91:2616–20.
Toyokuni S, Luo XP, Tanaka T, Uchida K, Hiai H, Lehotay DC. Induction of a wide range of C2–12 aldehydes and C7–12 acyloins in the kidney of Wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate. Free Radic Biol Med. 1997;22:1019–27.
Kawai Y, Furuhata A, Toyokuni S, Aratani Y, Uchida K. Formation of acrolein-derived 2’-deoxyadenosine adduct in an iron-induced carcinogenesis model. J Biol Chem. 2003;278(50):50346–54.
Tanaka T, Kondo S, Iwasa Y, Hiai H, Toyokuni S. Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress. Am J Pathol. 2000;156(6):2149–57.
Hiroyasu M, Ozeki M, Kohda H, Echizenya M, Tanaka T, Hiai H, et al. Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis. Am J Pathol. 2002;160(2):419–24.
Bollinger JM Jr, Edmondson DE, Huynh BH, Filley J, Norton JR, Stubbe J. Mechanism of assembly of the tyrosyl radical-dinuclear iron cluster cofactor of ribonucleotide reductase. Science. 1991;253(5017):292–8.
Cotruvo JA, Stubbe J. Class I Ribonucleotide Reductases: Metallocofactor Assembly and Repair In Vitro and In Vivo. Ann Rev Biochem. 2011;80:733–67.
Ito F, Nishiyama T, Shi L, Mori M, Hirayama T, Nagasawa H, et al. Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. Biochem Biophys Res Commun. 2016;476(4):600–6.
Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M et al. O2(-) and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017;31(4):487–500 e488.
Toyokuni S, Okamoto K, Yodoi J, Hiai H. Persistent oxidative stress in cancer. FEBS Lett. 1995;358:1–3.
Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008;68(5):1303–9.
Taguchi K, Yamamoto M. The KEAP1-NRF2 System in Cancer. Front Oncol. 2017;7:85.
Motooka Y, Toyokuni S. Ferroptosis as ultimate target of cancer therapy. Antioxid Redox Signal. 2022. https://doi.org/10.1089/ars.2022.0048.
Toyokuni S, Miyake N, Hiai H, Hagiwara M, Kawakishi S, Osawa T, et al. The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct. FEBS Lett. 1995;359(2–3):189–91.
Ozeki M, Miyagawa-Hayashino A, Akatsuka S, Shirase T, Lee WH, Uchida K, et al. Susceptibility of actin to modification by 4-hydroxy-2-nonenal. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;827(1):119–26.
Zheng H, Jiang L, Tsuduki T, Conrad M, Toyokuni S. Embryonal erythropoiesis and aging exploit ferroptosis. Redox Biol. 2021;48: 102175.
Van Do B, Gouel F, Jonneaux A, Timmerman K, Gele P, Petrault M, et al. Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis. 2016;94:169–78.
Masaldan S, Bush AI, Devos D, Rolland AS, Moreau C. Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. 2019;133:221–33.
Proneth B, Conrad M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. 2019;26(1):14–24.
Vogelstein B, Kinzler KW. The genetic basis of human cancer. New York: McGraw-Hill; 1998.
Toyokuni S. Oxidative stress as an iceberg in carcinogenesis and cancer biology. Arch Biochem Biophys. 2016;595:46–9.
Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997;278(5340):1043–50.
Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004;4(9):665–76.
Evans DG, Barwell J, Eccles DM, Collins A, Izatt L, Jacobs C, et al. The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services. Breast Cancer Res. 2014;16(5):442.
Momozawa Y, Sasai R, Usui Y, Shiraishi K, Iwasaki Y, Taniyama Y, et al. Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants. JAMA Oncol. 2022;8(6):871–8.
Casella D, Di Taranto G, Marcasciano M, Sordi S, Kothari A, Kovacs T, et al. Nipple-sparing bilateral prophylactic mastectomy and immediate reconstruction with TiLoop((R)) Bra mesh in BRCA1/2 mutation carriers: A prospective study of long-term and patient reported outcomes using the BREAST-Q. Breast. 2018;39:8–13.
Metcalfe K, Eisen A, Senter L, Armel S, Bordeleau L, Meschino WS, et al. International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation. Br J Cancer. 2019;121(1):15–21.
Miller LD, Coffman LG, Chou JW, Black MA, Bergh J, D’Agostino R Jr, et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res. 2011;71(21):6728–37.
Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM. Iron and Cancer. Annu Rev Nutr. 2018;38:97–125.
Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K, et al. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin Cancer Res. 2008;14(1):32–40.
Kobayashi H, Yamashita Y, Iwase A, Yoshikawa Y, Yasui H, Kawai Y et al. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. Fertil Steril. 2012;98(2):415–422 e411–412.
Mori M, Ito F, Shi L, Wang Y, Ishida C, Hattori Y, et al. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Redox Biol. 2015;6:578–86.
Kajiyama H, Suzuki S, Yoshihara M, Tamauchi S, Yoshikawa N, Niimi K, et al. Endometriosis and cancer. Free Radic Biol Med. 2019;133:186–92.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.
Evers B, Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene. 2006;25(43):5885–97.
Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci U S A. 2007;104(29):12111–6.
Nakamura Y, Kubota J, Nishimura Y, Nagata K, Nishimura M, Daino K, et al. Brca 1(L63X) (/+) rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer. Cancer Sci. 2022;113(10):3362–75.
Akatsuka S, Li GH, Toyokuni S. Superiority of rat over murine model for studies on the evolution of cancer genome. Free Radic Res. 2018;52(11–12):1323–7.
Okada S, Midorikawa O. Induction of rat renal adenocarcinoma by Fe-nitrilotriacetate (Fe-NTA). Jpn Arch Intern Med. 1982;29:485–91.
Kong Y, Akatsuka S, Motooka Y, Zheng H, Cheng Z, Shiraki Y, et al. BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance. Redox Biol. 2022;54: 102356.
Cheng Z, Akatsuka S, Li GH, Mori K, Takahashi T, Toyokuni S. Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis. Cancer Sci. 2022;113(1):65–78.
Li GH, Akatsuka S, Chew SH, Jiang L, Nishiyama T, Sakamoto A, et al. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. Pathol Int. 2017;67(11):564–74.
Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S. High incidence of allelic loss on chromosome 5 and inactivation of p15 INK4B and p16 INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats. Oncogene. 1999;18:3793–7.
Inagaki-Kawata Y, Yoshida K, Kawaguchi-Sakita N, Kawashima M, Nishimura T, Senda N, et al. Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants. Commun Biol. 2020;3(1):578.
Chen Y, Olopade OI. MYC in breast tumor progression. Expert Rev Anticancer Ther. 2008;8(10):1689–98.
Grushko TA, Dignam JJ, Das S, Blackwood AM, Perou CM, Ridderstrale KK, et al. MYC is amplified in BRCA1-associated breast cancers. Clin Cancer Res. 2004;10(2):499–507.
Luo Y, Akatsuka S, Motooka Y, Kong Y, Zheng H, Mashimo T, et al. BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis-resistance. Cancer Sci. 2022. https://doi.org/10.1111/cas.15705.
The author (YK) would like to take this opportunity to thank the “Interdisciplinary Frontier Next-Generation Researcher Program of the 10 Tokai Higher Education and Research System.” The authors thank Division for Medical Research Engineering, Nagoya University Graduate School of Medicine for technical assistance.
Conflict of interest
This work was supported, in part, by JST CREST (Grant Number JPMJCR19H4) and JSPS Kakenhi (Grant Number JP19H05462 and JP20H05502) to ST. This work was financially supported by JST SPRING, Grant Number JPMJSP2125 to YK.
Ethics approval and consent to participate
Consent for publication
All the authors agreed to an author of this review article.
All the authors declare no conflict of interest to present.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Toyokuni, S., Kong, Y., Motooka, Y. et al. Environmental impact on carcinogenesis under BRCA1 haploinsufficiency. Genes and Environ 45, 2 (2023). https://doi.org/10.1186/s41021-023-00258-5