Numerous observations suggest that chromosome instability is caused by mitotic abnormalities such as errors in the partitioning of chromosomes. Chfr was recently defined as a central component of a new mitotic checkpoint that delays chromosome condensation in response to mitotic stress. Chfr was shown to be frequently inactivated in several human neoplasms, including colon, lung and esophageal cancers. To test whether Chfr inactivation may lead or participate to chromosomal instability (CIN), we analysed the genetic and epigenetic status of the gene in a large panel of primary colon and breast cancers, as well as in colon and breast cancer cell lines displaying either a microsatellite instability or a CIN. Our results confirm that Chfr is frequently inactivated in colon cancers, through a mechanism of hypermethylation of the promoter sequences. In contrast, the loss of Chfr expression appears to be a rare event in breast cancers. Furthermore, our data demonstrate that Chfr inactivation is not associated with CIN in these frequent types of human cancers.
Despite its increasing clinical use, almost no data are currently available about paclitaxel effects on non-cancerous mammary epithelial cells. We have previously established paclitaxel-resistant sub-cell lines (paclitaxel-surviving populations, PSPs; n ¼ 20), and sensitive controls (control clones, CCs; n ¼ 10), from the untransformed human mammary epithelial cell line HME1. In this study, we aimed to establish whether paclitaxel resistance was associated with a modified sensitivity to paclitaxel-induced aneuploidy. For this purpose, we analysed basal and paclitaxel-induced chromosome missegregation, apoptosis and aberrant spindle multipolarisation as well as microtubular network composition for each subline. PSP sublines showed higher basal and paclitaxel-induced chromosome missegregation than the CC sublines. This phenomenon was associated with resistance to paclitaxel-induced apoptosis. No significant difference in paclitaxel-induced spindle pole abnormalities between CC and PSP sublines was found. Besides, we showed that a majority of PSPs display a constitutively disrupted microtubular network composition due to aberrant tubulin expression and posttranslational modifications. These results clearly indicate that paclitaxel resistance in untransformed human mammary epithelial cells is related to an increased susceptibility to acquire aneuploidy in response to this agent. The consequences of these paclitaxel-associated alterations could be deleterious as they can potentially trigger tumorigenesis. British Journal of Cancer (2007) (Colella et al, 1999;Branch et al, 2000). However, increased genetic damages could also have adverse consequences if the affected cells are not malignant. In fact, it has been previously shown that genetic instability, characterised by an abnormal number of chromosomes, is associated with secondary malignancies. Thus, consideration of the potential aneugenicity of chemotherapy to humans is a necessary adjunct to its clinical use.Paclitaxel is a chemotherapeutic agent that is frequently used in several human cancers, including lung, ovarian and breast cancer. Several previous works have addressed the aneugenic potential of this agent in various in vitro and in vivo models (Tinwell and Ashby, 1994;Jagetia and Adiga, 1995;Jagetia and Nayak, 1996;Digue et al, 1999;Galmarini et al, 2007). However, despite its increasing use, almost no data are currently available concerning its effects in normal human mammary epithelial cells. In a precedent work, we described that sub-cell lines of untransformed human mammary epithelial cells (HME1) were able to survive to a 1-week paclitaxel treatment (paclitaxel-surviving populations, PSPs) (Galmarini et al, 2006). In most of these sublines, the emergence of a transitory or stable drug resistance phenotype was related to the inactivation of p21/WAF1 protein.In this study, we sought to determine whether paclitaxel resistance could be related to a modified sensitivity to paclitaxel aneugenicity. For this purpose, we firstly assayed whether paclitaxel tre...
Cancers arise from the sequential acquisition of genetic alterations in specific genes. The high number of mutations in cancer cells led to the hypothesis that an early step in tumor progression is the generation of a genetic instability. The potent role of genetic instability in initiation and progression of colorectal cancers has been well defined in hereditary nonpolyposis colon cancer (HNPCC) syndrome. HNPCC is a common hereditary disorder caused by germline mutations of DNA mismatch repair (MMR) genes. Somatic loss of the normal allele of the predisposition gene leads to a strong "mutator phenotype", characterized by a high rate of mutations in repetitive sequences. Nevertheless, the observation of frequent alterations of key growth regulatory genes in MMR-deficient cells such as NF1, APC, p53, K-Ras, with no significant excess of frameshift mutations and changes at short coding repeats, suggest that even in the presence of an inherited tendency to genomic instability, tumor progression is mainly driven by a process of natural selection.
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