In situ analyses of genome instability in breast cancer

Abstract

Transition through telomere crisis is thought to be a crucial event in the development of most breast carcinomas. Our goal in this study was to determine where this occurs in the context of histologically defined breast cancer progression. To this end, we assessed genome instability (using fluorescence in situ hybridization) and other features associated with telomere crisis in normal ductal epithelium, usual ductal hyperplasia, ductal carcinoma in situ and invasive cancer. We modeled this process in vitro by measuring these same features in human mammary epithelial cell cultures during ZNF217-mediated transition through telomere crisis and immortalization. Taken together, the data suggest that transition through telomere crisis and immortalization in breast cancer occurs during progression from usual ductal hyperplasia to ductal carcinoma in situ.The molecular events that enable normal epithelial cells to progress to invasive, metastatic disease are increasingly well understood 1,2 . Deregulation of the TP53 and RB1 pathways in most cancers enables extended proliferation. In breast cancer, deregulation of RB1 through inactivation of cyclin-dependent kinase inhibitor 2A (CDKN2A, also called p16 and INK4a) seems to be an early event 3 . Most epithelial cells

Telomere dysfunction and tumour suppression: the senescence connection

“…Recent observations indicate that both telomere dysfunction 73,74 and the DDR 75,76 are activated at the earliest stages in many human carcinomas. The results presented would predict that activation of an intact DDR pathway by dysfunctional telomeres in premalignant lesions would engage cellular senescence or apoptotic pathways, suppressing further tumor progression.…”

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

“…On the other hand, studies on mice lacking the telomerase RNA gene demonstrate that critical telomere shortening and telomere instability can favor initial stages of cancer formation and cooperates with p53 deficiency to favor carcinogenesis Rudolph et al, 2001). In human tumorigenesis, a burst of telomere instability could occur at early stages as a consequence of an excessive telomere shortening and checkpoint inactivation (Rudolph et al, 2001;O'Sullivan et al, 2002;Chin et al, 2004;Zhang et al, 2004). This scenario is in agreement with the increased tumor susceptibility of patients carrying mutations in genes involved in chromosome stability and telomere maintenance (Callen and Surralles, 2004).…”

Genetic variation in five genes important in telomere biology and risk for breast cancer

“…As cells progress through the latter stages of carcinogenesis, telomeres become relatively stable. In addition, low-telomere DNA content was found to be an independent predictor of decreased survival in comparisons of breast cancer specimens to normal tissues (Chin et al, 2004;Fordyce et al, 2006).…”

“…Tumour cells may survive cellular crisis in the absence of chromosomal stability through the activation or inactivation of alternative pathways. Breast cancer fits the paradigm of dysfunctional telomere-induced genomic instability, because the transition of breast duct hyperplasia to ductal carcinoma in situ likely results from a period of telomere crisis (DePinho, 2000;Chin et al, 2004). As breast cancer progresses further to invasive and metastatic stages, telomere dysfunction and genomic instability become more apparent (Nishizaki et al, 1997;Buerger et al, 1999;Chin et al, 2004).…”