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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.
Highlights
Breast cancer, the second leading cause of cancer-related death among women in the United States, is often associated with defects in cell cycle checkpoint regulation
Densitometry analysis revealed that 41% (9 of 22) of asynchronous breast cancer cell (BCC) lines seemed to have low or no Checkpoint with FHA and Ring Finger (CHFR) expression compared with the lowest amount of expression observed among four immortalized human mammary epithelial cells (IHMEC) cell lines, whereas only one cell line, MDA-MB-157, had expression higher than the range observed in IHMEC cells (Fig. 1A)
Quantitative reverse transcription-PCR (RT-PCR) was used to better define the levels of CHFR mRNA from asynchronous BCC lines compared with IHMECs. mRNA was collected from cells at 70% to 80% confluency, the same confluency used for Northern blot analysis
Summary
The second leading cause of cancer-related death among women in the United States, is often associated with defects in cell cycle checkpoint regulation. Checkpoint with FHA and Ring Finger (CHFR) is a checkpoint protein that reportedly initiates a cell cycle delay in response to microtubule stress during prophase in mitosis [1]. This delay is thought to occur before chromosome condensation by excluding cyclin B1 from the nucleus [2]. One form of microtubule stress is treatment with taxanes, such as nocodazole or paclitaxel (Taxol), a chemotherapeutic drug used for cancer patients, including those with breast cancer [3]. The molecular mechanism by which CHFR initiates a cell cycle arrest is debated, evidence implicates the p38/mitogen-activated protein kinase pathway, an Aurora A interaction, and/or through regulation of PLK-1 [8,9,10,11]
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