Tumor suppressor function of RUNX3 in breast cancer

Chen, Lin Feng

doi:10.1002/jcb.24074

Cited by 49 publications

(51 citation statements)

References 74 publications

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“…A growing body of literature suggests that RUNX3 plays an important role in normal immune system development [56,57], susceptibility to early life disease as a result of in utero exposures [41], and many cancers [58-68]. RUNX3 is important for normal cellular differentiation and development, including T-cell differentiation [56,57,66,69], macrophage differentiation [70], neuronal cell development [71] and cell-cycle progression [63], and is known to negatively regulate dendritic cell maturation [72].…”

Section: Discussionmentioning

confidence: 99%

“…RUNX3 is important for normal cellular differentiation and development, including T-cell differentiation [56,57,66,69], macrophage differentiation [70], neuronal cell development [71] and cell-cycle progression [63], and is known to negatively regulate dendritic cell maturation [72]. RUNX3 is a tumor suppressor gene [58,60,62,67,73,74] and it interacts with β-catenin [61]. When upregulated, RUNX3 is known to inhibit cyclins D1 and E and increase p27, Rb and TIMP-1 expression [59,60].…”

Section: Discussionmentioning

confidence: 99%

“…RUNX3 expression changes are associated with clear cell renal cell carcinoma [60] and hepatocellular carcinoma [68]. RUNX3 hypermethylation is associated with cancers of the breast [58], stomach [63-65], prostate [75] and lung [76], as well as many others [77]. It has also been demonstrated that hypermethylation of RUNX3 in smokers is associated with bladder cancer [78].…”

Section: Discussionmentioning

confidence: 99%

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Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

et al. 2013

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Aims The developmental origins of health and disease hypothesis states that later-life disease may be influenced by the quality of the in utero environment. Environmental toxicants can have detrimental effects on fetal development, potentially through effects on placental development and function. Maternal smoking during pregnancy is associated with low birth weight, preterm birth and other complications, and exposure to cigarette smoke in utero has been linked to gross pathologic and molecular changes to the placenta, including differential DNA methylation in placental tissue. The aim of this study was to investigate the relationship between maternal smoking during pregnancy, methylation changes in the placenta and gestational age. Materials & methods We used Illumina®’s (CA, USA) Human Methylation27 BeadChip technology platform to investigate the methylation status of 21,551 autosomal, non-SNP-associated CpG loci in DNA extracted from 206 human placentas and examined loci whose variation in methylation was associated with maternal smoking during pregnancy. Results We found that methylation patterns of a number of loci within the RUNX3 gene were significantly associated with smoking during pregnancy, and one of these loci was associated with decreased gestational age (p = 0.04). Conclusion Our findings, demonstrating maternal smoking-induced changes in DNA methylation at specific loci, suggest a mechanism by which in utero tobacco smoke exposure could exert its detrimental effects upon the health of the fetus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

et al. 2013

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“…The RUNX3 gene, localized to chromosome 1p36, a region that exhibits frequent loss-of-heterozygosity events in colon, gastric, breast, and ovarian cancers, is considered a tumor-suppressor gene involved in the transforming growth factor beta (TGF-β) signaling pathway 13. Its precise function has been intensively studied in several tumors, with upregulation of the induction of cell-cycle arrest, apoptosis, and downregulation of cyclin D1 expression 14–18. Inactivation of RUNX3 by promoter methylation (hypermethylation) has been found to play an important role in colorectal epithelial tumorigenesis 19–21.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance and association of RUNX3 hypermethylation frequency with colorectal cancer: a meta-analysis

Mu¹,

Wang²,

Niu³

et al. 2014

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BackgroundThe RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor family and is closely involved in a variety of cellular processes including development, differentiation, participation in the regulation of p53-dependent DNA damage response and/or tumorigenesis. Emerging evidence indicates that RUNX3 is a candidate tumor suppressor in several types of human tumors including colorectal cancer (CRC). However, the correlation of RUNX3 inactivation with CRC remains unclear. In the study reported here, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of RUNX3 hypermethylation/expression on the incidence of CRC.MethodsA detailed search of the literature was made using Medline® and Web of Science for related research publications written in English. The methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of the pooled data were performed. Odds ratios (ORs) and hazard ratios were calculated and summarized, respectively.ResultsA final analysis of 1,427 CRC patients from eleven eligible studies was performed. We observed that RUNX3 hypermethylation was significantly higher in CRC than in normal colorectal mucosa. The pooled OR from six studies comprising 289 CRC and 188 normal colorectal mucosa was OR =0.07 (confidence interval [CI] =0.03–0.18, P<0.00001). Aberrant RUNX3 hypermethylation/expression was significantly higher in advanced CRC than in early staged CRC (OR =0.54, CI =0.41–0.71, P<0.0001). Aberrant RUNX3 hypermethylation/expression was also significantly higher in microsatellite instability (MSI)-positive CRC than in MSI-negative CRC (OR =0.44, CI =0.3–0.66, P<0.0001). In addition, CRC patients with RUNX3 hypermethylation or lacking RUNX3 protein expression had a lower survival rate than those without RUNX3 hypermethylation or those who did not express RUNX3 protein.ConclusionThe results of this meta-analysis suggest that RUNX3 hypermethylation is associated with an increased risk of CRC, increased risk of progression of CRC, and a poorer CRC survival rate. RUNX3 hypermethylation, which induces the inactivation of RUNX3 gene, plays an important role in colorectal carcinogenesis, high levels of MSI, as well as CRC progression and development.

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“…This discrepancy between the current state of mechanistic knowledge (represented in the DEABM) and the recognized real-world preponderance of ER+ cancers led us to posit that a key functional gap in the current state of knowledge concerning breast tumorigenesis was in accounting for the control structure governing the proliferative potential of ER+ cells. This recognition led to a model-driven search for a putative mechanism by which ER+ luminal epithelial cells could be made to divide, which subsequently identified the function of runt-related transcription factor 3 (RUNX3) as having a potential role in the origin of ER+ tumors [ 23 ]–[ 25 ]. The details of this process will be more comprehensively described in the Materials & Methods .…”

Section: Introductionmentioning

confidence: 99%

Examining the Pathogenesis of Breast Cancer Using a Novel Agent-Based Model of Mammary Ductal Epithelium Dynamics

et al. 2013

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The study of the pathogenesis of breast cancer is challenged by the long time-course of the disease process and the multi-factorial nature of generating oncogenic insults. The characterization of the longitudinal pathogenesis of malignant transformation from baseline normal breast duct epithelial dynamics may provide vital insight into the cascading systems failure that leads to breast cancer. To this end, extensive information on the baseline behavior of normal mammary epithelium and breast cancer oncogenesis was integrated into a computational model termed the Ductal Epithelium Agent-Based Model (DEABM). The DEABM is composed of computational agents that behave according to rules established from published cellular and molecular mechanisms concerning breast duct epithelial dynamics and oncogenesis. The DEABM implements DNA damage and repair, cell division, genetic inheritance and simulates the local tissue environment with hormone excretion and receptor signaling. Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells. The DEABM reproduced cellular population dynamics seen during the menstrual cycle and pregnancy, and demonstrated the oncogenic effect of known genetic factors associated with breast cancer, namely TP53 and Myc, in simulations spanning ∼40 years of simulated time. Simulations comparing normal to BRCA1-mutant breast tissue demonstrated rates of invasive cancer development similar to published epidemiologic data with respect to both cumulative incidence over time and estrogen-receptor status. Investigation of the modeling of ERα-positive (ER+) tumorigenesis led to a novel hypothesis implicating the transcription factor and tumor suppressor RUNX3. These data suggest that the DEABM can serve as a potentially valuable framework to augment the traditional investigatory workflow for future hypothesis generation and testing of the mechanisms of breast cancer oncogenesis.

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Tumor suppressor function of RUNX3 in breast cancer

Cited by 49 publications

References 74 publications

Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

Placental DNA Methylation Alterations Associated with Maternal Tobacco Smoking at the RUNX3 Gene are also Associated with Gestational Age

Clinical significance and association of RUNX3 hypermethylation frequency with colorectal cancer: a meta-analysis

Examining the Pathogenesis of Breast Cancer Using a Novel Agent-Based Model of Mammary Ductal Epithelium Dynamics

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