Telomerase activity in ductal carcinoma in situ of the breast

Shpitz, Baruch; Zimlichman, Shulamit; Zemer, Ruth; Bomstein, Yonit; Zehavi, Tania; Liverant, Sigal; Bernehim, J; Kaufman, Z; Klein, Ehud; Shapira, Y.; Klein, Ami

doi:10.1023/a:1006394209922

Cited by 42 publications

(23 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Much evidence suggests that genome instability is an early event in carcinogenesis (Nishizaki et al 1997;Kolquist et al 1998;Al-Mulla et al 1999;Buerger et al 1999;Shpitz et al 1999;Artandi and Depinho 2000;Romanov et al 2001). Chromosome rearrangements, such as those we observed, may promote transformation by mutation or altered regulation of genes at or near breakpoints and by altering gene dosage through large-scale duplication and deletion.…”

Section: Discussionmentioning

confidence: 60%

Telomere Loss Provokes Multiple Pathways to Apoptosis and Produces Genomic Instability inDrosophila melanogaster

Titen

Golic

2008

Genetics

View full text Add to dashboard Cite

Telomere loss was produced during development of Drosophila melanogaster by breakage of an induced dicentric chromosome. The most prominent outcome of this event is cell death through Chk2 and Chk1 controlled p53-dependent apoptotic pathways. A third p53-independent apoptotic pathway is additionally utilized when telomere loss is accompanied by the generation of significant aneuploidy. In spite of these three lines of defense against the proliferation of cells with damaged genomes a small fraction of cells that have lost a telomere escape apoptosis and divide repeatedly. Evasion of apoptosis is accompanied by the accumulation of karyotypic abnormalites that often typify cancer cells, including end-to-end chromosome fusions, anaphase bridges, aneuploidy, and polyploidy. There was clear evidence of bridge-breakage-fusion cycles, and surprisingly, chromosome segments without centromeres could persist and accumulate to highcopy number. Cells manifesting these signs of genomic instability were much more frequent when the apoptotic mechanisms were crippled. We conclude that loss of a single telomere is sufficient to generate at least two phenotypes of early cancer cells: genomic instability that involves multiple chromosomes and aneuploidy. This aneuploidy may facilitate the continued escape of such cells from the normal checkpoint mechanisms.

show abstract

Section: Discussionmentioning

confidence: 60%

Telomere Loss Provokes Multiple Pathways to Apoptosis and Produces Genomic Instability inDrosophila melanogaster

Titen

Golic

2008

Genetics

View full text Add to dashboard Cite

show abstract

“…DeCapri, and R.A. Weinberg, in prep.). Because most breast cancers maintain their telomeres by the activation of telomerase activity (Shpitz et al 1999), the ectopic expression of hTERT described here closely mimics a change that occurs during the progression of spontaneously arising breast cancers. Lastly, although the ras gene is rarely mutated in breast cancers (∼5% of cases), evidence suggests that most breast cancers have alterations in the Ras-signaling pathway (Clark and Der 1995), one common mechanism being overexpression of HER-2/neu, a known upstream activator of Ras signaling.…”

Section: Discussionmentioning

confidence: 82%

Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells

Elenbaas¹,

Spirio²,

Koerner³

et al. 2001

Genes Dev.

796

835

View full text Add to dashboard Cite

“…Although the former activity may be important in the majority of human cancers, the latter activity may promote carcinogenesis in only a subset of tissues, including the mammary gland and skin. Notably, whereas telomerase is up-regulated in most human solid tumors at the invasive stage, in breast cancers, telomerase is reactivated in 80-90% of cases at the preinvasive ductal carcinoma in situ (DCIS) stage (36), and hTERT mRNA is similarly up-regulated in nearly 100% cases of DCIS (37). Reactivation of telomerase at this stage may both stabilize telomeres and promote growth and maturation of these incipient lesions.…”

Section: Increased Mterc and Telomerase Activity In Mtert Tg Mammarymentioning

confidence: 99%

Constitutive telomerase expression promotes mammary carcinomas in aging mice

Artandi

Alson

Tietze

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

284

172

View full text Add to dashboard Cite

Telomerase is up-regulated in the vast majority of human cancers and serves to halt the progressive telomere shortening that ultimately blocks would-be cancer cells from achieving a full malignant phenotype. In contrast to humans, the laboratory mouse possesses long telomeres and, even in early generation telomerase-deficient mice, the level of telomere reserve is sufficient to avert telomere-based checkpoint responses and to permit full malignant progression. These features in the mouse provide an opportunity to determine whether enforced high-level telomerase activity can serve functions that extend beyond its ability to sustain telomere length and function. Here, we report the generation and characterization of transgenic mice that express the catalytic subunit of telomerase (mTERT) at high levels in a broad variety of tissues. Expression of mTERT conferred increased telomerase enzymatic activity in several tissues, including mammary gland, splenocytes, and cultured mouse embryonic fibroblasts. In mouse embryonic fibroblasts, mTERT overexpression extended telomere lengths but did not prevent culture-induced replicative arrest, thus reinforcing the view that this phenomenon is not related to occult telomere shortening. Robust telomerase activity, however, was associated with the spontaneous development of mammary intraepithelial neoplasia and invasive mammary carcinomas in a significant proportion of aged females. These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve.

show abstract

Telomerase activity in ductal carcinoma in situ of the breast

Cited by 42 publications

References 23 publications

Telomere Loss Provokes Multiple Pathways to Apoptosis and Produces Genomic Instability inDrosophila melanogaster

Telomere Loss Provokes Multiple Pathways to Apoptosis and Produces Genomic Instability inDrosophila melanogaster

Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells

Constitutive telomerase expression promotes mammary carcinomas in aging mice

Contact Info

Product

Resources

About