Telomerase activity in ductal carcinoma in situ and invasive breast cancer

Umbricht, Christopher B.; Sherman, Mark E.; Dome, Jeffrey S.; Carey, Lisa A.; Marks, J.; Kim, N.; Sukumar, Saraswati

doi:10.1038/sj.onc.1202714

Cited by 50 publications

(33 citation statements)

References 29 publications

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“…Moreover, a strong increase of hTERC expression was focally observed in CIS in close vicinity with invasive process implicating telomerase complex in malignant transformation and tumor invasion (24). Expression of hTERT subunit, which represents a limiting factor for telomerase activity, was also evaluated through telomerase activity measure and hTERT mRNA detection in preneoplastic lesions in short series of preinvasive bronchial lesions, including squamous metaplasia and dysplasia, levels increasing along with the severity of their grade (25 -27).…”

Section: Discussionmentioning

confidence: 99%

“…Telomerase is expressed early during the cervical, oral, breast, and colorectal carcinogenic process, predominating in high-grade invasive lesions (21,24,41). For instance, telomerase activity has been detected in nearly 70% of breast CIS (24), and elevated hTERT mRNA levels were detected by in situ hybridization in 40% of cervical intraneoplastic grade III lesions, where they correlated with the presence of high-risk human papillomavirus DNA (22).…”

Section: Discussionmentioning

confidence: 99%

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Telomere Shortening and Telomerase Reverse Transcriptase Expression in Preinvasive Bronchial Lesions

Lantuéjoul

Soria²,

Morat³

et al. 2005

Clinical Cancer Research

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Purpose: Telomerase, a ribonucleoprotein complex whose activity is related to the expression of its catalytic subunit human telomerase reverse transcriptase (hTERT), restores telomere length in tumor cells and enables immortality after p53/Rb inactivation has been achieved. To determine the timing of hTERT derepression during bronchial carcinogenesis and its relationship with telomere shortening and the p53/Rb pathway alterations, we did an immunohistochemical and in situ hybridization study in preinvasive and invasive bronchial lesions.Experimental Design: hTERT, P53, P16, cyclin D1, Baxto-Bcl2 ratio, and Ki67 immunostainings were done in 106 preneoplastic lesions and in paired lung carcinoma and normal bronchial mucosae. Concomitantly, hTERT mRNA levels and qualitative telomere shortening were assessed by in situ hybridization and fluorescence in situ hybridization, respectively, in a subset of preneoplastic and neoplastic lesions.Results: Telomerase was increasingly expressed from normal epithelium to squamous metaplasia, dysplasia, and carcinoma in situ, and decreased in invasive carcinoma (P < < < 0.0001), with a direct correlation between protein and mRNA levels of expression (P < < < 0.0001). hTERT expression was directly correlated with P53, Ki67, and Bcl2-to-Bax ratio, suggesting a coupling between telomerase reactivation, proliferation, and resistance to apoptosis. Telomere signals significantly decreased as early as squamous metaplasia and progressively increased over the spectrum of preneoplastic lesions.Conclusions: Telomere shortening represents an early genetic abnormality in bronchial carcinogenesis, preceding telomerase expression and p53/ /Rb inactivation, which predominate in high-grade preinvasive lesions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Telomere Shortening and Telomerase Reverse Transcriptase Expression in Preinvasive Bronchial Lesions

Lantuéjoul

Soria²,

Morat³

et al. 2005

Clinical Cancer Research

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“…28,29 Most significantly, the majority of DCIS have previously been shown to harbor telomerase activity. 30 Since telomerase reactivation is generally considered to be a mechanism of overcoming the growth-limiting effects of telomere shortening, it is not unexpected that DCIS would have short telomeres. Given that short telomeres have been associated with chromosome instability, it is tempting to speculate that those DCIS harboring very short telomeres are genetically unstable and predisposed to evolve toward invasive carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Telomere Shortening Occurs in Subsets of Normal Breast Epithelium as well as in Situ and Invasive Carcinoma

Meeker¹,

Hicks²,

Gabrielson³

et al. 2004

The American Journal of Pathology

135

121

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In the setting of inactivated DNA damage-sensitive checkpoints, critically shortened telomeres promote chromosomal instability and the types of widespread cytogenetic alterations that characterize most human carcinomas. Using a direct telomere fluorescence in situ hybridization technique, we analyzed 114 invasive breast carcinomas, 29 carcinoma in situ lesions, 10 benign proliferative lesions, and different normal epithelial components of the male and female breast. We found marked telomere shortening in the majority (52.5%) of invasive carcinomas; smaller subsets of invasive carcinoma demonstrated moderate telomere shortening (17.5%) or normal telomere lengths (21%), while a small subgroup (5%) contained elongated telomeres. Strikingly, the majority (78%) of ductal carcinoma in situ demonstrated markedly or moderately shortened telomeres. Surprisingly, unlike all other normal epithelia studied to date, moderate telomere shortening was observed in benign secretory cells in approximately 50% of histologically-normal terminal duct lobular units (from which most breast cancer is thought to arise), while such shortening was not seen in myoepithelial cells or normal large lactiferous ducts of the female breast or male breast ducts (from which breast cancer infrequently arises). We postulate that such shortening is the result of hormonally driven, physiological proliferation, and may delineate a population of epithelial cells at risk for subsequent malignant transformation.

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“…Genomic DNA was extracted by incubation of the microdissected cells at 458C612 h in 50 ml bu er containing 10 mM TrisCl (pH 8.0), 1 mM EDTA, 0.1% Tween 20, and 0.5 mg/ml proteinase K. Unless large numbers of sections can be processed, microdissected tissue samples of small lesions typically do not yield su cient amounts of DNA for quantitation by optical density at 260 nm. We have estimated yields in the range of several hundred genome equivalents per sample using semiquantitative PCR of genomic DNA as described in (Umbricht et al, 1999). Therefore, the entire DNA sample was submitted to MSP, and the presence of either methylated or unmethylated Figure 4 Nucleotide sequencing of 14-3-3-s-DNA following NaHSO3-treatment.…”

Section: Tissue Samplesmentioning

confidence: 99%

“…Samples of non-malignant breast lesions were retrieved as para nembedded tissue blocks from surgical pathology archives at the same institutions. Microdissection was performed by using a laser capture microscope (Emmert-Buck et al, 1996) or by manually scraping the cells with a 25G needle under 406magni®cation (Umbricht et al, 1999). Pairs of 8 mm cryosections or 4 mm para n sections were microdissected for DCIS and invasive cancers.…”

Section: Tissue Samplesmentioning

confidence: 99%

Hypermethylation of 14-3-3 σ (stratifin) is an early event in breast cancer

et al. 2001

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We have identi®ed 14-3-3 s (s) as a gene whose expression is lost in breast carcinomas, primarily by methylation-mediated silencing. In this report, we investigated the timing of loss of s gene expression during breast tumorigenesis in vivo. We analysed the methylation status of s in breast cancer precursor lesions using microdissection for selective tissue sampling. We found hypermethylation of s in 24 of 25 carcinomas (96%), 15 of 18 (83%) of ductal carcinoma in situ, and three of eight (38%) of atypical hyperplasias. None of the ®ve hyperplasias without atypia showed s-hypermethylation. Unexpectedly, patients with breast cancer showed s hypermethylation in adjacent histologically normal breast epithelium, while this was never observed in individuals without evidence of breast cancer. Also, samples of periductal stromal breast tissue were consistently hypermethylated, underscoring the importance of selective tissue sampling for accurate assessment of 14-3-3-s methylation in breast epithelium. These results suggest that hypermethylation of 14-3-3-s occurs at an early stage in the progression to invasive breast cancer, and may occur in apparently normal epithelium adjacent to breast cancer. These results provide evidence that loss of expression of s is an early event in neoplastic transformation. Oncogene (2001) 20, 3348 ± 3353.

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Telomerase activity in ductal carcinoma in situ and invasive breast cancer

Cited by 50 publications

References 29 publications

Telomere Shortening and Telomerase Reverse Transcriptase Expression in Preinvasive Bronchial Lesions

Telomere Shortening and Telomerase Reverse Transcriptase Expression in Preinvasive Bronchial Lesions

Telomere Shortening Occurs in Subsets of Normal Breast Epithelium as well as in Situ and Invasive Carcinoma

Hypermethylation of 14-3-3 σ (stratifin) is an early event in breast cancer

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