Tissue ferritin concentration and prognosis in carcinoma of the breast

Weinstein, Robert E.; Bond, Bernice H.; Silberberg, Boris; Vaughn, Clarence B.; Subbaiah, Perla; Pieper, David R.

doi:10.1007/bf01806307

Cited by 43 publications

(28 citation statements)

References 32 publications

(17 reference statements)

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“…In this study, we provide experimental evidence for this suggestion by demonstrating that human breast cancer cells, especially those with an aggressive mesenchymal phenotype, are characterized by pronounced up-regulation of ironregulatory proteins, including TF, IRP1, IRP2, FTL, and FTH1. Similar up-regulation of these iron-regulatory proteins in cancer cells, including breast cancer cells, has been documented in several previous studies [12][13][14][15][25][26][27][28][29][30][31][32].…”

Section: Discussionmentioning

confidence: 72%

Role of ferritin alterations in human breast cancer cells

Shpyleva

Tryndyak

Kovalchuk

et al. 2010

Breast Cancer Res Treat

171

153

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Breast cancer is the most common malignancy in women. Successful treatment of breast cancer relies on a better understanding of the molecular mechanisms involved in breast cancer initiation and progression. Recent studies have suggested a crucial role of perturbations in ferritin levels and tightly associated with this, the deregulation of intracellular iron homeostasis; however, the underlying molecular mechanisms for the cancer-linked ferritin alterations remain largely unknown and often with conflicting conclusions. Therefore, this study was undertaken to define the role of ferritin in breast cancer. We determined that human breast cancer cells with an epithelial phenotype, such as MCF-7, MDA-MB-361, T-47D, HCC70 and cells, expressed low levels of ferritin light chain, ferritin heavy chain, transferrin, transferring receptor, and iron-regulatory proteins 1 and 2. In contrast, expression of these proteins was substantially elevated in breast cancer cells with an aggressive mesenchymal phenotype, such as Hs-578T, BT-549, and especially MDA-MB-231 cells. The up-regulation of ferritin light chain and ferritin heavy chain in MDA-MB-231 cells was accompanied by alterations in the subcellular distribution of these proteins as characterized by an increased level of nuclear ferritin and a lower level of the cellular labile iron pool as compared to MCF-7 cells. We established that ferritin heavy chain is a target of miRNA miR-200b, suggesting that its up-regulation in MDA-MB-231 cells may be triggered by the low expression of miR-200b. Ectopic up-regulation of miR-200b by transfection of MDA-MB-231 cells with miR-200b substantially decreased the level of ferritin heavy chain. More importantly, miR-200b-induced down-regulation of ferritin was associated with an increased sensitivity of the MDA-MB-231 cells to the chemotherapeutic agent doxorubicin. These results suggest that perturbations in ferritin levels are associated with the progression of breast cancer toward a more advanced malignant phenotype.

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Section: Discussionmentioning

confidence: 72%

Role of ferritin alterations in human breast cancer cells

Shpyleva

Tryndyak

Kovalchuk

et al. 2010

Breast Cancer Res Treat

171

153

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“…However, it is well known that estrogen receptor positivity is more common in well differentiated tumors (which had higher levels of p43 in our study) [23]. of 'normal' ferritin (as found in liver and spleen) and dedifferentiation in breast cancer [4,5]. Contrary to Weinstein and coworkers, who described a significantly prolonged recurrence-free survival in breast cancer patients with low tissue concentrations of 'normal' ferritin, we found a significantly better outcome in patients with high values of PLF in their tumors.…”

Section: Discussionmentioning

confidence: 89%

“…However, previously published data have demonstrated controversial and conflicting results on the role of ferritin as a marker of prognosis, particularily for breast cancer. Some authors have reported that the determination of 'normal' ferritin in breast cancer tissue revealed six-fold higher levels than in non-malignant breast tissue and that high tissue concentrations of ferritin correlated with histopathologic dedifferentiation as well as with poor prognosis [4,5].…”

Section: Introductionmentioning

confidence: 99%

Placental isoferritin associated p43 antigen correlates with features of high differentiation in breast cancer

Rosén

Moroz

Reiner

et al. 1992

Breast Cancer Res Tr

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Placental isoferritin (PLF), an acidic isoform of ferritin, and its unique superheavy chain p43 have been recently described to be synthesized by breast cancer cell lines but not by normal breast epithelial cells. Since previous reports have demonstrated a correlation between the content of 'normal' ferritin in breast cancer tissue, degree of differentiation, and prognosis, we have tried to evaluate the correlation of p43 in the cytosol of 122 breast cancer samples with commonly applied prognostic factors and features of proliferation and differentiation. In parallel, we investigated the correlation of p43 expression in MCF-7 and T47-D breast cancer cell lines during proliferation induced by estradiol plus fetal calf serum (assessed by 3H-thymidine incorporation), compared to p43 expression in stationary non-stimulated cell cultures. The levels of p43 in breast cancer cytosols correlated significantly negatively with tumor size (p = 0.0001), histologic grading (p = 0.0038), nuclear pleomorphism (p = 0.0019), rate of mitosis (p = 0.0002), and lymphocytic reaction (p = 0.0001), and significantly directly with the estrogen receptor status (p = 0.0009). Although patients with a higher p43 content showed a trend for a better outcome (median follow-up: 61.4 months), an independent influence of the cytosolic p43 content on survival could not be confirmed by a multivariate Cox model. In accordance with the observed negative correlation of features of differentiation vs. p43 expression, induction of proliferation by estradiol plus FCS added to serum-free tissue culture medium correlated with a decrease of p43 synthesis in both cell lines. Expression of p43 in estrogen and FCS-absent media revealed also a decrease in relation to a low spontaneous proliferation. However, the drop of p43 synthesis was significantly stronger in cell lines with estrogen-stimulated proliferation. Our in vitro and cytosol results confirm recent clinical observations describing an inverse correlation of p43 synthesis with the degree of proliferation and differentiation in breast cancer. However, the pathologic mechanisms leading to this phenomenon as well as the negative correlation with lymphocytic infiltration are still unclear and need to be further elucidated.

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“…42 So far, FTL overexpression has been reported in several malignancies including colon and breast cancer as well as in a cell line derived from a metastatic lymph node. 43,44 Further, low levels of ferritin light chain have been shown to be associated with a good response in breast cancer. 45 In agreement with these data, we observed a significantly higher expression of FTL in osteosarcoma biopsies from patients with poor response to chemotherapy and consequently an association of FTL expression with therapy outcome.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of drug-regulated genes in high-grade osteosarcoma

et al. 2007

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About 25-45% of patients with high-grade osteosarcoma poorly respond to chemotherapy with an increased risk of relapse and the development of metastasis. Therefore, the aim of this study was the evaluation of the prognostic value of eight previously identified drug-regulated candidate genes on osteosarcoma therapy outcome. Gene expression of 8 candidate genes was analyzed in 35 formalin-fixed, paraffin-embedded, lasermicrodissected osteosarcoma biopsies. The prognostic value of these genes was evaluated by the correlation of gene expression with therapy outcome, overall survival and event-free survival in univariate and multivariate analysis. Upon univariate analysis, the expression of MALAT-1, IMPDH2, FTL and RHOA significantly correlated with response to chemotherapy. Expression of all four genes was increased in the poor responder group. Upon multivariate analysis, IMPDH2 maintained its independent prognostic value (P ¼ 0.025). Concerning the overall survival of the patients, we observed a significant association with the expression of FTL, PHB, ATAD2, ACTN1 and RRM2 as well as lactate dehydrogenase serum levels. In the subgroups of patients with high expression of these genes and those with elevated lactate dehydrogenase levels, the mean overall survival was decreased 1.7-, 1.9-, 2.2-, 2.4-, 1.5-and 4.5-fold, respectively. Except RRM2, all genes and lactate dehydrogenase serum levels remained significant in the multivariate analysis. In addition, the event-free survival was significantly decreased in the subgroups of patients with high FTL, ATAD2 and IMPDH2 expression (1.8-, 6.3-and 2.4-fold, respectively). These data demonstrate that among the identified genes are valuable markers for the prediction of osteosarcoma therapy outcome. Especially IMPDH2 and FTL are promising candidates for the stratification of osteosarcoma patients into low-and high-risk groups. Owing to their involvement in drug action these genes may further be potential targets for the modulation of drug sensitivity.

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Tissue ferritin concentration and prognosis in carcinoma of the breast

Cited by 43 publications

References 32 publications

Role of ferritin alterations in human breast cancer cells

Role of ferritin alterations in human breast cancer cells

Placental isoferritin associated p43 antigen correlates with features of high differentiation in breast cancer

Prognostic significance of drug-regulated genes in high-grade osteosarcoma

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