Regulation of SELENOF translation by eIF4a3: Possible role in prostate cancer progression.

The levels of the SELENOF selenoprotein are dramatically reduced in prostate cancer compared to adjacent benign tissue and reducing SELENOF in prostate epithelial cells results in the acquisition of features of the transformed phenotype. It was hypothesized that the aberrant increase in the eiF4a3 translation factor, which has an established role in RNA splicing and the regulation of selenoprotein translation, contributes to the lower levels of SELENOF. Using the available databases, eIF4a3 messenger RNA (mRNA) levels are elevated in prostate cancer compared to normal tissue as is the hypomethylation of the corresponding gene. Using a prostate cancer tissue microarray, we established that eiF4a3 levels are higher in prostate cancer tissue. Ectopic expression of eIF4a3 in prostate cancer cells reduced SELENOF levels and attenuated the readthrough of the UGA codon using a specialized reporter construct designed to examine UGA decoding, with the opposite effects observed using eIF4a3 knock-down constructs. Direct binding of eIF4a3 to the regulatory regions of SELENOF mRNA was established with pull-down experiments. Lastly, we show that an eIF4a3 inhibitor, eIF4a3-IN-2, increases SELENOF levels, UGA readthrough, and reduces binding of eIF4a3 to the SELENOF mRNA 3'-UTR in exposed cells. These data establish eIF4a3 as a likely prostate cancer oncogene and a regulator of SELENOF translation.

Associations of selenoprotein expression and gene methylation with the outcome of clear cell renal carcinoma.

Selenoproteins are a ubiquitous class of proteins defined by having a selenocysteine amino acid residue. While many of the selenoproteins have been well characterized with important roles in oxidation-reduction reactions and hormone synthesis among others, there exist some whose biological roles are not as well understood as denoted by the "SELENO" root. In this study, we explored associations between the reported RNA levels of "SELENO" proteins and clear cell renal cell carcinoma (ccRCC), the most common subtype of renal carcinoma in the US. Utilizing The Cancer Genome Atlas (TCGA) alongside other in silico tools, we discovered higher mRNA expression of Selenoprotein I, T, and P was associated with better overall survival outcomes and differential expression of other selenoproteins based on tumor stage. Additionally, we uncovered relative hypomethylation among selenoproteins in primary ccRCC tumor samples compared to normal tissue. Network and enrichment analysis showed numerous genes through which selenoproteins may modulate cancer progression and outcomes such as DERL1, PNPLA2/3, MIEN1, and FOXO1 which have been well-described in other cancers. In light of our findings highlighting an association of selenoprotein methylation and expression patterns with ccRCC outcome, further wet lab research is warranted.

Role of SELENBP1 and SELENOF in prostate cancer bioenergetics.

The contribution of selenium and selenoproteins in prostate cancer etiology remains elusive, potentially due to insufficient information regarding the biochemical pathways in which they are involved. There are twenty-five human selenocysteine-containing proteins or selenoproteins as well as a smaller class of selenium-containing proteins that do not include selenocysteine, and their cancer-associated aberrations, both genetic and functional, have evoked special interest, although their contribution to the metabolic reprogramming of prostate cancers remains has not been extensively studied. While benign prostate tissue exhibits a glycolytic phenotype, neoplastic events restore the truncated tricarboxylic acid cycle and enhance oxidative phosphorylation. Two selenium-containing proteins, selenium binding protein 1 and selenoprotein F, affect prostate cancer phenotypes by modulating tumor cell metabolic profiles with significant effects on mitochondrial biology, including oxidative phosphorylation and ATP synthesis. One of the pathways affected by both proteins is the activation of adenosine monophosphate kinase and its downstream signaling with concomitant induction of glycolysis. This review focuses on highlighting the role of these two proteins in modulating the bioenergetic profile of prostate cancer and in maintaining the metabolic plasticity of these cells rendering growth advantage and possible therapeutic resistance.

Loss of SELENOF Induces the Transformed Phenotype in Human Immortalized Prostate Epithelial Cells.

SELENOF is a member of the class of selenoproteins in which the amino acid selenocysteine is co-translationally inserted into the elongating peptide in response to an in-frame UGA codon located in the 3'-untranslated (3'-UTR) region of the SELENOF mRNA. Polymorphisms in the 3'-UTR are associated with an increased risk of dying from prostate cancer and these variations are functional and 10 times more frequent in the genomes of African American men. SELENOF is dramatically reduced in prostate cancer compared to benign adjacent regions. Using a prostate cancer tissue microarray, it was previously established that the reduction of SELENOF in the cancers from African American men was significantly greater than in cancers from Caucasian men. When SELENOF levels in human prostate immortalized epithelial cells were reduced with an shRNA construct, those cells acquired the ability to grow in soft agar, increased the ability to migrate in a scratch assay and acquired features of energy metabolism associated with prostate cancer. These results support a role of SELENOF loss in prostate cancer progression and further indicate that SELENOF loss and genotype may contribute to the disparity in prostate cancer mortality experienced by African American men.

Selenium-binding protein 1 alters energy metabolism in prostate cancer cells.

OBJECTIVE: The broad goal of the research described in this study was to investigate the contributions of selenium-binding protein 1 (SBP1) loss in prostate cancer development and outcome. METHODS: SBP1 levels were altered in prostate cancer cell lines and the consequences on oxygen consumption, expression of proteins associated with energy metabolism, and cellular transformation and migration were investigated. The effects of exposing cells to the SBP1 reaction products, H2 O2 and H2 S were also assessed. In silico analyses identified potential HNF4α binding sites within the SBP1 promoter region and this was investigated using an inhibitor specific for that transcription factor. RESULTS: Using in silico analyses, it was determined that the promoter region of SBP1 contains putative binding sites for the HNF4α transcription factor. The potential for HNF4α to regulate SBP1 expression was supported by data indicating that HNF4α inhibition resulted in a dose-response increase in the levels of SBP1 messenger RNA and protein, identifying HNF4α as a novel negative regulator of SBP1 expression in prostate cancer cells. The consequences of altering the levels of SBP1 were investigated by ectopically expressing SBP1 in PC-3 prostate cancer cells, where SBP1 expression attenuated anchorage-independent cellular growth and migration in culture, both properties associated with transformation. SBP1 overexpression reduced oxygen consumption in these cells and increased the activation of AMP-activated protein kinase (AMPK), a major regulator of energy homeostasis. In addition, the reaction products of SBP1, H2 O2 , and H2 S also activated AMPK. CONCLUSIONS: Based on the obtained data, it is hypothesized that SBP1 negatively regulates oxidative phosphorylation (OXPHOS) in the healthy prostate cells by the production of H2 O2 and H2 S and consequential activation of AMPK. The reduction of SBP1 levels in prostate cancer can occur due to increased binding of HNF4α, acting as a transcriptional inhibitor to the SBP1 promoter. Consequently, there is a reduction in H2 O2 and H2 S-mediated signaling, inhibition of AMPK, and stimulation of OXPHOS and building blocks of biomolecules needed for tumor growth and progression. Other effects of SBP1 loss in tumor cells remain to be discovered.

Subcellular compartmentalization of glutathione peroxidase 1 allelic isoforms differentially impact parameters of energy metabolism.

Specific genetic variations in the gene for the selenium-containing antioxidant protein glutathione peroxidase 1 (GPX1) are associated with the risk of a variety of common diseases, including cancer, diabetes, and cardiovascular disorders. Two common variations have been focused upon, one resulting in leucine or proline at codon 198 and another resulting in 5, 6, or 7 alanine repeats were previously shown to affect the distribution of GPX1 between the cytoplasm and mitochondria. Human MCF7 cells engineered to exclusively express GPX1 with five alanine repeats at amino terminus and proline at codon 198 (A5P) and seven alanine repeats at amino terminus and leucine at codon 198 (A7L), as well as derivatives targeted to the mitochondria by the addition of a mitochondrial localization sequence (mA5P and mA7L) were used to assess the consequences of the expression of these proteins on the cellular redox state and bioenergetics. Ectopic expression of A5P and A7L reduced the levels of reactive oxygen species, and the mitochondrially targeted derivatives exhibited better activity in these assays. Bioenergetics and mitochondrial integrity were assessed by measuring mitochondrial membrane potential, oxygen consumption, adenosine triphosphate (ATP) levels, and the levels of lactate dehydrogenase. The results of these assays indicated distinctively, and sometimes opposing, patterns with regard to differences between the consequences of the expression of A5P, A7L, mA5P, and mA7L. These data provide new information on the consequences of differences in the primary structure and cellular location of GPX1 proteins and contribute to the understanding of how these effects might contribute to human disease.

Interaction of NKX3.1 and SELENOP genotype with prostate cancer recurrence.

BACKGROUND: NKX3.1 is a tumor suppressor frequently lost in prostate cancer. Previous studies by others indicated that the risks associated with reduced NKX3.1 levels can be enhanced by anti-oxidant supplementation. Selenium is an essential component of several proteins with anti-oxidant functions and lower levels of selenium have been associated with greater risk of prostate cancer. In contrast, participants of the select prostate cancer prevention trial were at increased risk of prostate cancer when supplemented with selenium when their baseline selenium levels were high. METHODS: In order to investigate whether there was an interaction between a functional polymorphism in NKX3.1 that results in less protein and selenium status with prostate cancer grade or outcome, plasma selenium levels and the genotypes of NKX3.1 and the selenium carrier protein SELENOP were determined from a cohort of men who underwent radical protatectomy. RESULTS: NKX3.1 and SELENOP genotypes were associated with a more aggressive prostate tumor grade at the time of prostatectomy, but there were no significant interactions of NKX3.1 genotype with either selenium status or SELENOP genotype. There was also a significant association between NKX3.1 genotype and prostate cancer recurrence, however this association was modified by SELENOP genotype, but not with plasma selenium levels. CONCLUSIONS: These data indicate that the impact of selenium status on prostate cancer may be influenced by factors other than the amount of selenium in circulation.

An unsupervised neuromorphic clustering algorithm.

Brains perform complex tasks using a fraction of the power that would be required to do the same on a conventional computer. New neuromorphic hardware systems are now becoming widely available that are intended to emulate the more power efficient, highly parallel operation of brains. However, to use these systems in applications, we need "neuromorphic algorithms" that can run on them. Here we develop a spiking neural network model for neuromorphic hardware that uses spike timing-dependent plasticity and lateral inhibition to perform unsupervised clustering. With this model, time-invariant, rate-coded datasets can be mapped into a feature space with a specified resolution, i.e., number of clusters, using exclusively neuromorphic hardware. We developed and tested implementations on the SpiNNaker neuromorphic system and on GPUs using the GeNN framework. We show that our neuromorphic clustering algorithm achieves results comparable to those of conventional clustering algorithms such as self-organizing maps, neural gas or k-means clustering. We then combine it with a previously reported supervised neuromorphic classifier network to demonstrate its practical use as a neuromorphic preprocessing module.

Correlations of SELENOF and SELENOP genotypes with serum selenium levels and prostate cancer.

BACKGROUND: Selenium status is inversely associated with the incidence of prostate cancer. However, supplementation trials have not indicated a benefit of selenium supplementation in reducing cancer risk. Polymorphisms in the gene encoding selenoprotein 15 (SELENOF) are associated with cancer incidence/mortality and present disproportionately in African Americans. Relationships among the genotype of selenoproteins implicated in increased cancer risk, selenium status, and race with prostate cancer were investigated. METHODS: Tissue microarrays were used to assess SELENOF levels and cellular location in prostatic tissue. Sera and DNA from participants of the Chicago-based Adiposity Study Cohort were used to quantify selenium levels and genotype frequencies of the genes for SELENOF and the selenium-carrier protein selenoprotein P (SELENOP). Logistic regression models for dichotomous patient outcomes and regression models for continuous outcome were employed to identify both clinical, genetic, and biochemical characteristics that are associated with these outcomes. RESULTS: SELENOF is dramatically reduced in prostate cancer and lower in tumors derived from African American men as compared to tumors obtained from Caucasians. Differing frequency of SELENOF polymorphisms and lower selenium levels were observed in African Americans as compared to Caucasians. SELENOF genotypes were associated with higher histological tumor grade. A polymorphism in SELENOP was associated with recurrence and higher serum PSA. CONCLUSIONS: These results indicate an interaction between selenium status and selenoprotein genotypes that may contribute to the disparity in prostate cancer incidence and outcome experienced by African Americans.

Selenium-Binding Protein 1 in Human Health and Disease.

Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of SBP1, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented.

Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which drive oncogenesis.

Reactive oxygen species (ROS) largely originating in the mitochondria play essential roles in the metabolic and (epi)genetic reprogramming of cancer cell evolution towards more aggressive phenotypes. Recent studies have indicated that the activity of superoxide dismutase (SOD2) may promote tumor progression by serving as a source of hydrogen peroxide (H2O2). H2O2 is a form of ROS that is particularly active as a redox agent affecting cell signaling due to its ability to freely diffuse out of the mitochondria and alter redox active amino acid residues on regulatory proteins. Therefore, there is likely a dichotomy whereas SOD2 can be considered a protective antioxidant, as well as a pro-oxidant during cancer progression, with these effects depending on the accumulation and detoxification of H2O2. Glutathione peroxidase-1 GPX1, is a selenium-dependent scavenger of H2O2 which partitions between the mitochondria and the cytosol. Epidemiologic studies indicated that allelic variations in the SOD2 and GPX1 genes alter the distribution and relative concentrations of SOD2 and GPX1 in mitochondria, thereby affecting the dynamic between the production and elimination of H2O2. Experimental and epidemiological evidence supporting a conflicting role of SOD2 in tumor biology, and epidemiological evidence that SOD2 and GPX1 can interact to affect cancer risk and progression indicated that it is the net accumulation of mitochondrial H2O2 (mtH2O2) resulting from of the balance between the activities SOD2 and anti-oxidants such as GPX1 that determines whether SOD2 prevents or promotes oncogenesis. In this review, research supporting the idea that GPX1 is a gatekeeper restraining the oncogenic power of mitochondrial ROS generated by SOD2 is presented. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Selenoprotein Gene Nomenclature.

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

A Critical Role for Cysteine 57 in the Biological Functions of Selenium Binding Protein-1.

The concentration of selenium-binding protein1 (SBP1) is often lower in tumors than in the corresponding tissue and lower levels have been associated with poor clinical outcomes. SBP1 binds tightly selenium although what role selenium plays in its biological functions remains unknown. Previous studies indicated that cysteine 57 is the most likely candidate amino acid for selenium binding. In order to investigate the role of cysteine 57 in SBP1, this amino acid was altered to a glycine and the mutated protein was expressed in human cancer cells. The SBP1 half-life, as well as the cellular response to selenite cytotoxicity, was altered by this change. The ectopic expression of SBP1(GLY) also caused mitochondrial damage in HCT116 cells. Taken together, these results indicated that cysteine 57 is a critical determinant of SBP1 function and may play a significant role in mitochondrial function.

L-selenomethionine does not protect against testosterone plus 17ß-estradiol-induced oxidative stress and preneoplastic lesions in the prostate of NBL rats.

Previous animal studies examining dietary selenium effects on prostatic carcinogenesis did not show preventive benefit, including 1 study in a rat model involving testosterone (T) and estradiol (E2)-induced prostatic oxidative stress. Here, we examined modulation of T + E2-induced prostatic oxidative stress, dysplasia, and inflammation by L-selenomethionine at 1.5 or 3.0 mg selenium/kg in NIH-07 diet in Noble (Nbl)/Crl rats treated with T + E2 for 16 wk. Hormone treatment increased immunohistochemical staining for 8-hydroxydeoxyguanosine (8-OHdG) in the prostatic sites of T + E2-induced preneoplasia (P < 0.05), but selenomethionine did not attenuate 8-OHdG staining and dysplasia in the lateral prostate. Glutathione-peroxidase activity (P < 0.05) and mRNA expression were induced by T + E2 (P < 0.0001) but not changed by selenomethionine. Selenomethionine did not cause significant responses in expression and activity of glutathione-peroxidase and MnSOD, except for a reduction of MnSOD protein expression in the lateral prostate (P < 0.01). The absence of reduction of oxidative stress and dysplasia and the minimal effects on antioxidant enzymes caused by selenomethionine are consistent with the null effects observed in selenium supplementation animal studies and clinical trials. Significant (P < 0.01) opposite apoptosis/cell proliferation balance responses to selenomethionine and to T + E2 occurred in the lateral and dorsal prostate, explaining why T + E2 induces lesions selectively in the lateral lobe of NBL rats.

Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention?

The trace element selenium is an essential micronutrient that has received considerable attention for its potential use in the prevention of cancer. In spite of this interest, the mechanism(s) by which selenium might function as a chemopreventive remain to be determined. Considerable experimental evidence indicates that one possible mechanism by which selenium supplementation may exert its benefits is by enhancing the DNA damage repair response, and this includes data obtained using cultured cells, animal models as well as in human clinical studies. In these studies, selenium supplementation has been shown to be beneficial in reducing the frequency of DNA adducts and chromosome breaks, consequentially reducing the likelihood of detrimental mutations that ultimately contribute to carcinogenesis. The benefits of selenium can be envisioned as being due, at least in part, to it being a critical constituent of selenoproteins such as glutathione peroxidases and thioredoxin reductases, proteins that play important roles in antioxidant defence and maintaining the cellular reducing environment. Selenium, therefore, may be protective by preventing DNA damage from occurring as well as by increasing the activity of repair enzymes such as DNA glycosylases and DNA damage repair pathways that involve p53, BRCA1 and Gadd45. An improved understanding of the mechanism of selenium's impact on DNA repair processes may help to resolve the apparently contradicting data obtained from decades of animal work, human epidemiology and more recently, clinical supplementation studies.

Distinct Roles of SELENOF in Different Human Cancers.

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF's discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF's molecular mechanisms and its impact on cancer is warranted.

Reticulocyte mitochondrial retention increases reactive oxygen species and oxygen consumption in mouse models of sickle cell disease and phlebotomy-induced anemia.

Sickle cell disease (SCD) is caused by a mutation of the ß-globin gene that results in the production of hemoglobin S (HbS). People with SCD experience anemia, severe acute pain episodes, persistent chronic pain, multiorgan damage, and a reduced life span. The pathophysiology of SCD caused by the polymerization of HbS on deoxygenation results in red cell deformability and the generation of reactive oxygen species (ROS). These 2 factors lead to red cell fragility and hemolysis. Reticulocytosis is an independent predictor of disease morbidity and mortality in SCD. We previously established that humans and mice with SCD exhibit abnormal mitochondrial retention in erythrocytes increasing ROS-associated hemolysis. Here, we investigated the hypothesis that mitochondrial retention and increased ROS are a consequence of stress erythropoiesis. Our results show clearly that stress erythropoiesis in phlebotomized, anemic AA mice results in mitochondrial retention and increased ROS in reticulocytes. We observed that elevated mitochondrial retention in reticulocytes also alters oxygen consumption and potentially contributes to increased HbS polymerization and red blood cell hemolysis. Therefore, these events occurring due to stress erythropoiesis contribute significantly to the pathology of SCD and suggest new therapeutic targets.

Inverse association between glutathione peroxidase activity and both selenium-binding protein 1 levels and Gleason score in human prostate tissue.

BACKGROUND: Data from human epidemiological studies, cultured mammalian cells, and animal models have supported a potentially beneficial role of selenium (Se) in prostate cancer prevention. In addition, Se-containing proteins including members of the glutathione peroxidase (GPx) family and Selenium-Binding Protein 1 (SBP1) have been linked to either cancer risk or development. For example, SBP1 levels are typically reduced in tumors compared to non-cancerous tissue, with the degree of reduction associated with increasingly poor clinical outcome. METHODS: In order to investigate inter-relationships between blood and tissue Se levels and GPx activity, tissue SBP1 levels, and disease aggressiveness using the Gleason score, we measured levels of selenium and selected selenoproteins in fasting serum and histologically normal prostate tissues obtained from 24 men undergoing radical prostatectomy for the treatment of localized prostate cancer. RESULTS: GPx enzyme activity was inversely correlated with SBP1 levels in prostate tissue as determined by densitometry of Western blots obtained using anti-SBP1 antibodies [partial Spearman's correlation coefficients and corresponding P-values overall and in African-Americans = -0.42 (0.08) and -0.53 (0.10), respectively], which is consistent with previous observations in cultured cells and mice. Of particular interest was the positive correlation between tissue GPx activity and Gleason score, with this relationship achieving statistical significance among African-Americans (r = 0.67, P = 0.02). CONCLUSION: These studies support the continued investigation of the role of Se and selenoproteins in prostate cancer prevention, development, and prognosis.

SELENOF is a new tumor suppressor in breast cancer.

Epidemiological evidence has indicated an inverse association between selenium status and various types of cancer, including breast cancer. Selenoproteins are the primary mediators of selenium effects in human health. We have previously reported loss of heterozygosity in breast tumor samples of the gene for one of the selenoproteins, SELENOF. The function of SELENOF remains unclear and whether SELENOF levels impact breast cancer risk or outcome is unknown. The mining of breast cancer patient databases revealed that SELENOF mRNA is significantly lower in late-stage tumor samples and lower levels of SELENOF also predict poor patient outcome from breast cancer. Genetically manipulating SELENOF in human breast cancer cells or in the murine mammary gland by overexpression, silencing or knockout impacted cell viability by affecting both proliferation and cell death. Restoring SELENOF can attenuate a number of aggressive cancer phenotypes in breast cancer cells, including clonogenic survival, and enhance the response to drugs or radiation used in breast cancer therapy. Importantly, enhancing SELENOF expression reduced in vivo tumor growth in a murine xenograft model of breast cancer. These data indicate that SELENOF is a new tumor suppressor in breast cancer.