Altered Expression of the Early Mitotic Checkpoint Protein, CHFR, in Breast Cancers: Implications for Tumor Suppression

Privette, Lisa M.; González, María E.; Ding, Lei; Kleer, Celina G.; Petty, Elizabeth M.

doi:10.1158/0008-5472.can-06-4109

Cited by 44 publications

(35 citation statements)

References 37 publications

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“…CHFR mRNA expression is frequently disturbed in a variety of solid tumors, 12,[14][15][16][17][18][19] and the mechanism of this disturbance often results from aberrant methylation of the promoter region. [14][15][16][17][18][19] Regardless of the frequent inactivation of the CHFR gene in human malignancies, the impacts of this phenomenon on clinical outcomes are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Both genetic and epigenetic mechanisms have been thought to be responsible for the inactivation of checkpoint-related genes in human cancer. [31][32][33] Regarding CHFR, epigenetic inactivation is frequently seen, though the range varies from 10 to 61% in each form cancer, [14][15][16][17][18][19] however, genetic mutations are very rare in NSCLC. 16 In this study, the promoter methylation of the CHFR gene was detected in 3 of 20 (15%) cases of NSCLC, in accordance with previous reports, 16,17 and these cases were accompanied by decreases in both mRNA and protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…After mRNA extraction, reverse transcription and real-time quantitative RT-PCR were carried out in each case. The data were then compared to the immunohistochemical protein expression in matched formalin-fixed and paraffin-embedded tissue (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Various levels of messenger RNA expression of the CHFR were detected in NSCLC (Fig.…”

Section: Correlation Between Mrna and Immunohistochemical Protein Expmentioning

confidence: 99%

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CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

Takeshita

Koga

Takayama

et al. 2008

Intl Journal of Cancer

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Loss of tumor suppressors and activation of oncogenes lead to carcinogenesis. Abnormal expression of CHFR, a novel checkpoint gene, or of Aurora kinases, key regulators of mitosis, has been detected in a variety of solid tumors. Recently, CHFR has been revealed to ensure chromosomal stability by controlling the expression level of Aurora-A in vitro. However, the frequency of aberrant expression of these proteins and the association with clinicopathologic parameters remain poorly defined in nonsmall-cell lung cancer (NSCLC). In this study, we investigated the immunohistochemical protein expression of CHFR and Aurora-A in 157 NSCLC cases and evaluated the association between clinicopathologic parameters statistically. The relationship between CHFR protein and mRNA levels and the association between this relationship and promoter methylation of the CHFR gene were also examined in 20 frozen sections of NSCLC. Overexpression of Aurora-A and reduced expression of CHFR were found in 94 cases (59.8%) and 62 cases (39%) of NSCLC, respectively, and those were significantly correlated with tumor differentiation and size. Moreover, diminished CHFR expression was significantly associated with smoking-related squamous cell carcinoma cases and poor prognosis. Multivariate analysis revealed that CHFR expression was an independent prognostic factor. A statistical correlation was evident between CHFR protein and mRNA expression. In conclusion, our results suggest the aberrant expression of Aurora-A and/or of CHFR contributed to the increase in the malignant potential of NSCLC. We also revealed that CHFR expression was predominantly impaired in smoking-related squamous cell carcinoma and might be a useful prognostic marker in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Correlation Between Mrna and Immunohistochemical Protein Expmentioning

confidence: 99%

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CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

Takeshita

Koga

Takayama

et al. 2008

Intl Journal of Cancer

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“…Mutations in the Chfr gene have been identified in a variety of human cancers, including lung, nasopharyngeal, gastric and breast tumors, leading to the suggestion that Chfr is a tumor suppressor gene candidate (Mizuno et al, 2002;Cheung et al, 2003;Corn et al, 2003;Erson and Petty, 2003;Mariatos et al, 2003). In support of this, the knockdown of Chfr in immortalized mammary epithelial cells results in a malignant phenotype with cells displaying increased growth rates, invasiveness and colony formation, whereas knockout mice are cancer-prone (Mariatos et al, 2003;Yu et al, 2005;Privette et al, 2007).…”

Section: Introductionmentioning

confidence: 98%

Chfr interacts and colocalizes with TCTP to the mitotic spindle

et al. 2008

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Chfr is a checkpoint protein that plays an important function in cell cycle progression and tumor suppression, although its exact role and regulation are unclear. Previous studies have utilized overexpression of Chfr to determine the signaling pathway of this protein in vivo. In this study, we demonstrate, by using three different antibodies against Chfr, that the endogenous and highly overexpressed ectopic Chfr protein is localized and regulated differently in cells. Endogenous and lowly expressed ectopic Chfr are cytoplasmic and localize to the spindle during mitosis. Higher expression of ectopic Chfr correlates with a shift in the localization of this protein to the nucleus/PML bodies, and with a block of cell proliferation. In addition, endogenous and lowly expressed ectopic Chfr is stable throughout the cell cycle, whereas when highly expressed, ectopic Chfr is actively degraded during S-G2/ M phases in an autoubiquitination and proteasome-dependent manner. A two-hybrid screen identified TCTP as a possible Chfr-interacting partner. Biochemical analysis with the endogenous proteins confirmed this interaction and identified b-tubulin as an additional partner for Chfr, supporting the mitotic spindle localization of Chfr. The Chfr-TCTP interaction was stable throughout the cell cycle, but it could be diminished by the complete depolymerization of the microtubules, providing a possible mechanism where Chfr could be the sensor that detects microtubule disruption and then activates the prophase checkpoint.

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“…However, very little work has focused on function of the FHA domain by interactions with multiple transcriptional regulators. Recently, decreased CHFR expression in breast cancer cells was found to result in phenotypes associated with malignant progression, including amplified anchorageindependent colony formation, increased motility and enhanced invasiveness (Privette et al, 2007). However, the mechanisms underlying the effects of CHFR on the motility and invasiveness of cancer cells are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

et al. 2009

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The mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger domains) is silenced in various human cancers by promoter hypermethylation, suggesting that CHFR is a tumor suppressor. Here, we show that CHFR functions as a negative regulator of the nuclear factor-jB (NF-jB) pathway. Expression of CHFR inhibited NF-jB reporter activity, whereas knockdown of CHFR activated reporter activity. These activities are independent of its RING finger domain. Furthermore, we found that CHFR physically interacts with p65 in cells. Electrophoretic mobility shift assays (EMSAs) and ELISA-based NF-jB-binding assays showed that CHFR negatively regulated transcriptional activity of p65. In addition, our data show that interleukin (IL)-8 is significantly downregulated by CHFR, and that the migration of human endothelial cells is suppressed in culture medium conditioned from CHFR-expressing cancer cells. Using a xenograft model, we show that neovascularization is suppressed by adenovirus-mediated transfer of CHFR. These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-jB. As the NF-jB signaling pathway plays a critical role in the development and progression of cancer, our findings show the functional relationship between epigenetic alteration and inflammation/angiogenesis in human cancer cells, thereby showing several potential targets for therapeutic intervention.

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Altered Expression of the Early Mitotic Checkpoint Protein, CHFR, in Breast Cancers: Implications for Tumor Suppression

Abstract: Checkpoint with FHA and Ring

Cited by 44 publications

References 37 publications

CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

Chfr interacts and colocalizes with TCTP to the mitotic spindle

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

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