An Iron Regulatory Gene Signature Predicts Outcome in Breast Cancer

Miller, Lance D.; Coffman, Lan; Chou, Jeff W.; Black, Michael A.; Bergh, Jonas; D’Agostino, Ralph B.; Torti, Suzy V.; Torti, Frank M.

doi:10.1158/0008-5472.can-11-1870

Cited by 182 publications

(191 citation statements)

References 34 publications

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“…In recent years, the role and mechanisms of breast cancerrelated abnormalities in iron metabolism have been investigated in a variety of experimental and clinical settings (11,(32)(33)(34), with particular emphasis on altering the dependence of cancer cells on iron as a potential therapeutic strategy for the treatment of tumors and/or increasing the efficacy of anti-cancer agents (17,35,36). This strategy is driven largely by the well-established fact that neoplastic cells have an increased requirement for iron, as well as recent evidence demonstrating that 'high intracellular iron phenotype' is associated with poor prognosis in breast cancer patients (33).…”

Section: Discussionmentioning

confidence: 99%

“…1). The reduction in JMJD2A levels following DFO treatment was not a surprising discovery, since JMJD2A belongs to the superfamily of iron-dependent oxygenases (11). This suggests that the down-regulation of JMJD2A is associated directly with the iron chelating properties of DFO; however, in the DFO-treated MCF-7 cells, HIF1α may also actively contribute to this effect (38), since it was moderately up-regulated (Fig.…”

Section: Mcf-7mentioning

confidence: 90%

“…Both of these processes are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed (9,10). For instance, it is well-established that changes in cellular iron metabolism play a crucial role in the progression of many types of cancer (9), including breast cancer (11), suggesting that deregulated iron metabolism in malignant cells may be a promising molecular target for cancer therapy. Similarly, the dysregulation of epigenetic mechanisms is regarded as one of the hallmarks of cancer (12,13) and correcting the enzymatic processes that control the epigenome has emerged as a novel epigenetic approach for the treatment of cancer (13).…”

Section: Modulation Of Intracellular Iron Metabolism By Iron Chelatiomentioning

confidence: 99%

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Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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Abstract. Iron plays a vital role in the normal functioning of cells via the regulation of essential cellular metabolic reactions, including several DNA and histone-modifying proteins. The metabolic status of iron and the regulation of epige netic mechanisms are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed. Cancer-related abnormalities in iron metabolism have been corrected through the use of iron-chelating agents, which cause an inhibition of DNA synthesis, G 1 -S phase arrest, an inhibition of epithelial-to-mesenchymal transition, and the activation of apoptosis. In the present study, we show that, in addition to these well-studied molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO), a model iron chelator, causes significant epigenetic alterations at the global and gene-specific levels. Specifically, DFO treatment decreased the protein levels of the histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A (JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the levels of the histone H3 lysine 4 demethylase, lysine-specific demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were accompanied by alterations in corresponding metabolically sensitive histone marks. Additionally, we demonstrate that DFO treatment activates apoptotic programs in MCF-7 and MDA-MB-231 cancer cells and enhances their sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin; however, the mechanisms underlying this activation differ. The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-dependent, triggered mainly by the down-regulation of the JMJD2A histone demethylase, while in mutant TP53 MDA-MB-231 cells, the activation of the p53-independent apoptotic program was driven predominantly by the epigenetic up-regulation of p21. IntroductionA growing body of evidence indicates the existence of an intimate link between the metabolic status and epigenetic regulation of cells (1,2). This is exemplified by the fact that a variety of small molecules involved in intercellular metabolism, including adenosine triphosphate, S-adenosylmethionine, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, folate, acetyl coenzyme A, α-ketoglutarate and iron, are essential for the proper maintenance of the cellular epigenome.Iron is an essential trace element for normal cellular function. In addition to its significance in controlling a variety of cellular processes, including proliferation, DNA synthesis and repair, and mitochondrial electron transport, which are essential for the accurate maintenance of normal cellular homeostasis, iron plays a key regulatory role in the functioning of DNA and histone-modifying proteins (3,4). Specifically, the Jumonji domain-containing histone demethylase (JHDM) family, which catalyzes the demethylation of tri-and dimethylated lysine 9 and lysine 36 residues in histone H3 (5,6) and ten-eleven tra...

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Section: Discussionmentioning

confidence: 99%

Section: Mcf-7mentioning

confidence: 90%

Section: Modulation Of Intracellular Iron Metabolism By Iron Chelatiomentioning

confidence: 99%

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Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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“…Tumor cells were also noted to express hepcidin and its receptor ferroportin [15,16]. Moreover, reduced ferroportin expression correlated with poor prognosis, with a better survival rate for patients with high ferroportin levels in cancer patients [13,17]. Nonetheless, studies of the adaptive metabolism for tumor iron that facilitates cell growth are still rare, and the molecular mechanisms responsible for abnormal regulation of hepcidin/ferroportin in tumor cells remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Zhang

Chen

Guo

et al. 2014

Cellular Signalling

109

136

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Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth.

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“…FPN mutations would lead to iron overload and consequently to diseases associated with either low or normal transferrin saturation [10,11]. Mounting evidence unravels that dysregulation of FPN may also contribute to cancer development including hepatocellular carcinoma and breast cancers [12][13][14]. For instance, reduced FPN expression was found to correlate with poor prognosis, whereas a better survival rate was associated with breast cancer patients with high FPN levels [13].…”

Section: Introductionmentioning

confidence: 99%