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Published on: February 17, 2011
Altered expression of the early mitotic checkpoint protein, CHFR, in breast cancers: implications for tumor
Lisa M Privette1, Maria E González, Lei Ding
1Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0638, USA.
Abstract:
Checkpoint with FHA and Ring Finger (CHFR) is hypothesized to mediate a delay in cell cycle progression early in mitosis in response to microtubule stress, independent of the spindle assembly checkpoint. As a potential regulator of cell cycle progression, CHFR naturally becomes an interesting target for understanding cancer cells. In recent years, there has been increasing evidence supporting the role of CHFR as a tumor suppressor, most of which report loss of expression, occasionally due to promoter hypermethylation, in cancers compared with patient-matched normal tissues. We studied both a panel of breast cancer cell lines as well as primary tissue samples from breast cancer patients to investigate CHFR as a relevant tumor suppressor in breast cancer and to determine whether CHFR expression was associated with clinical and pathologic variables. We report that 41% of cell lines and 36% of patient samples showed low or negative CHFR protein expression or staining. In addition, lack of CHFR detection was associated with increased tumor size and weakly correlated with estrogen receptor-negative tumors from patients. To study the effects of low CHFR expression in vitro, we stably expressed a short hairpin RNA construct targeting CHFR in two lines of immortalized human mammary epithelial cells. Notably, decreased CHFR expression resulted in the acquisition of many phenotypes associated with malignant progression, including accelerated growth rates, higher mitotic index, enhanced invasiveness, increased motility, greater aneuploidy, and amplified colony formation in soft agar, further supporting the role of CHFR as a tumor suppressor in breast cancer.
Insights
Checkpoint with FHA and Ring Finger (CHFR) acts as a tumor suppressor in breast cancer. Loss of CHFR expression is linked to aggressive tumor features and promotes malignant progression, highlighting its critical role.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- Checkpoint with FHA and Ring Finger (CHFR) is a cell cycle regulator involved in mitotic checkpoint control.
- Evidence suggests CHFR functions as a tumor suppressor, with its expression often lost in various cancers.
- Loss of CHFR expression can be attributed to mechanisms like promoter hypermethylation.
Purpose of the Study:
- To investigate the role of CHFR as a tumor suppressor in breast cancer.
- To determine the association between CHFR expression and clinical-pathological variables in breast cancer patients.
- To elucidate the functional consequences of CHFR loss in breast cancer progression.
Main Methods:
- Analysis of CHFR protein expression in breast cancer cell lines and primary patient samples.
- Correlation of CHFR expression levels with clinical and pathological data.
- In vitro studies using RNA interference to deplete CHFR in immortalized human mammary epithelial cells.
Main Results:
- Reduced or absent CHFR protein expression was observed in 41% of cell lines and 36% of patient samples.
- Lack of CHFR expression correlated with larger tumor size and was weakly associated with estrogen receptor-negative status.
- In vitro depletion of CHFR led to phenotypes indicative of malignant progression, including increased growth, invasiveness, motility, aneuploidy, and anchorage-independent growth.
Conclusions:
- CHFR is a relevant tumor suppressor in breast cancer.
- Loss of CHFR expression is associated with adverse clinicopathological features and promotes malignant phenotypes.
- CHFR warrants further investigation as a potential therapeutic target in breast cancer treatment.
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