Telomerase Activity and Survival of Patients With Node-Positive Breast Cancer

Clark, Gary M.; Osborne, C. Kent; Levitt, Daniel; Wu, Fred; Kim, Nam W.

doi:10.1093/jnci/89.24.1874

Cited by 125 publications

(74 citation statements)

References 36 publications

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“…The previously reported correlation between telomerase and biological parameters such as patients age, tumor size, and DNA index (Clark et al, 1997) was again seen in the samples for which a quantitative assay was available. Telomerase activity was not signi®cantly higher in invasive cancer tissue than in DCIS if telomerase negative samples were excluded.…”

Section: Discussionmentioning

confidence: 59%

“…su cient to maintain telomeres, there is no selective advantage to increasing expression further. Also, the correlation between telomerase and DNA index (a measure of aneuploidy) and the lack of correlation with the S phase fraction (a measure of proliferation) suggests that telomerase is more than a simple proliferative index, although a relationship with proliferative indices has been detected in larger series (Clark et al, 1997) (Carey et al, in preparation, 1999). Figure 4 Telomerase activity of periductal in®ltrates vs DCIS.…”

Section: Discussionmentioning

confidence: 99%

“…The similar levels of telomerase activity seen in matched DCIS and cancer tissue (Figure 3) and the possible lack of prognostic implications of telomerase activity in early stages of invasive breast cancer (Carey et al, in preparation, 1999) suggest little bene®t to the cancer cell in overexpressing telomerase beyond what is necessary for telomerase maintenance, at least initially. This may not be the case in later stages of the disease, if high telomerase activity are associated with signi®cantly poorer outcomes in node-positive breast cancer (Clark et al, 1997). These data could be explained be a progressive perturbation of regulatory processes during cancer progression, such that reactivated telomerase activity would only initially be maintained at a level matching cellular needs.…”

Section: Discussionmentioning

confidence: 99%

“…Initial results suggested that smaller, lymph nodenegative tumors were more likely to be telomerasenegative than their larger, lymph node-positive counterparts (Hiyama et al, 1996;Kim et al, 1994), and it was postulated that telomerase activity is acquired during tumor progression to metastasis (Hiyama et al, 1996). More recently, some studies have found correlations between telomerase activity and stage, traditional prognostic indicators, and clinical outcome in invasive breast cancer (Clark et al, 1997;Hoos et al, 1998). Other studies, however, failed to show a correlation between telomerase activity and prognostic factors or clinical outcome in breast cancer (Bednarek et al, 1997;Carey et al, 1998;Nawaz et al, 1997;Sugino et al, 1996;Tsao et al, 1997) and (Carey et al, in preparation, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Telomerase activity in ductal carcinoma in situ and invasive breast cancer

et al. 1999

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The increasing number of breast carcinoma in situ detected by screening procedures makes it imperative to develop improved markers to stratify the risk of invasive cancer. Telomerase is detectable in invasive cancer, but not in normal tissues. We have microdissected frozen tissue blocks containing both DCIS and invasive cancer to assay the telomerase activity of these two lesions. The 46 available cases of concurrent DCIS and invasive breast cancer resulted in 43 DCIS samples and 38 invasive cancer samples adequate for analysis. Seventy per cent of the DCIS and all invasive cancer samples tested had detectable telomerase activity. In addition, we analysed telomerase activity in ten cases of DCIS that were not associated with invasive cancer, and detected telomerase activity in seven (70%). Mixing experiments showed no evidence of telomerase inhibitors in telomerase negative samples. Furthermore, periductal in¯ammatory in®ltrates were shown to be a potential confounding source of telomerase activity. Since DCIS lesions appear to be heterogeneous with respect to telomerase activity, and telomerase activation appears to precede the development of invasive cancer, telomerase activity may be a useful adjunct in stratifying the risk of developing invasive breast cancer in patients with DCIS.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Telomerase activity in ductal carcinoma in situ and invasive breast cancer

et al. 1999

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“…However, these markers remain unsatisfactory because of their low sensitivity and/or specificity or because of their limited applicability, for example, telomerase in breast lesions (Clark et al, 1997) or ret/PTC rearrangements in thyroid cancer (Cheung et al, 2001). The KOC assay is generally applicable and could be a useful novel tool to refine the FNA diagnosis of malignancy by reducing the number of additional procedures required to establish a suspected diagnosis of malignancy.…”

Section: Revised 15 October 2002; Accepted 28 November 2002mentioning

confidence: 99%

KOC is a novel molecular indicator of malignancy

et al. 2003

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The detection of malignant cells in fine-needle aspirates (FNA's) using marker genes is hampered by the fact that these markers are only expressed by certain malignancies or lack sensitivity and/or specificity. Here we report the results of a prospective pilot study examining the expression of KOC (KH-domain containing protein over expressed in cancer), a novel onco-foetal gene, in 76 patients who underwent fine-needle aspiration for further diagnosis of abdominal lesions, aszites, cysts or cerebrospinal fluid. Aspirates were examined by cytology and by a KOC RT -PCR assay. KOC expression was a highly sensitive and specific indicator of malignancy. The KOC assay could be useful to facilitate screening for malignant disease and to improve the diagnostic accuracy of FNAs. In a large-scale screen for differentially expressed genes in pancreatic cancer, we have recently identified a gene encoding a novel protein with four K-homologous (KH) domains, which is highly overexpressed in pancreatic cancer (Mueller-Pillasch et al, 1997). The new gene was named KOC (KH-domain containing protein overexpressed in cancer). Two known functions of KHdomain containing proteins are the regulation of mRNA stability and subcellular localisation, both of which are implicated in fundamental biological processes such as development, cell growth, differentiation and carcinogenesis (Ross et al, 1997). Therefore, KOC may play a role in the regulation of tumour cell proliferation by interfering with transcriptional and/or posttranscriptional processes. However, the precise role of KOC in tumour biology remains to be elucidated. Our preliminary data suggested that KOC is exclusively expressed in tumours and embryonic tissues (Mueller-Pillasch et al, 1997, 1999 and may therefore represent an ideal target for novel diagnostic approaches. To test this hypothesis, a prospective study was undertaken to determine the diagnostic accuracy of measuring KOC expression as compared to the cytological assessment in a consecutive series of fine-needle aspirates (FNAs) from abdominal lesions, aszites, various cysts and cerebrospinal fluid. MATERIALS AND METHODS Determination of KOC expression in cell lines and FNAsHuman Panc-1 pancreatic cancer cells were purchased from the American Type Culture Collection. Stocks were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (v v À1 ) foetal bovine serum (FBS) in a humidified atmosphere of 5% CO 2 /95% air at 371C and passaged every 3 days. Confluent cultures of Panc-1 cells were trypsinised and resuspended in serum-free DMEM. Various numbers of Panc-1 cells were subsequently mixed with 1 ml of human serum and then immediately centrifuged at 1200 r.p.m. for 2 min. The supernatants were decanted. The remaining cell pellets were resuspended in the RNeasy Mini Kit lysis buffer (Qiagen, Hilden, Germany) and total RNA was extracted using the same kit according to the manufacturer's instructions. cDNA synthesis and PCR were performed with the one-step RT -PCR (Polymerase Chain Reaction) Kit ...

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Differential telomerase activity, expression of the telomerase catalytic sub-unit and telomerase-RNA in ovarian tumors

Park

Riethdorf

et al. 1999

Int. J. Cancer

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Telomerase activity has been found in a variety of malignant tumors but only rarely in benign tumors or normal tissues. In this study, we investigated telomerase activation in 37 ovarian tumors, including benign, borderline and malignant neoplasms. Telomerase activity was detected using the telomeric repeat amplification protocol (TRAP) in 13/16 ovarian carcinomas, 9/10 borderline tumors and 3/11 cystadenomas/fibromas. mRNA expression of the putative human telomerase catalytic sub‐unit gene (hTERT) was detected by RT‐PCR in 14/15 ovarian carcinomas, 8/10 borderline tumors and 4/11 cystadenomas/fibromas. In situ hybridization was performed to evaluate telomerase‐RNA (hTR) expression in the corresponding paraffin‐embedded tumors. Variable expression levels of hTR were found over neoplastic tumor cells. The highest levels of hTR expression were found predominantly in ovarian carcinomas. Although the amount of telomerase activity varied, significantly high levels of telomerase activity were found predominantly in ovarian carcinomas. hTERT mRNA expression was closely associated with telomerase activity. These findings suggest that up‐regulation of hTERT and hTR is important for telomerase activation during malignant‐tumor progression. Telomerase activation might therefore be a valuable diagnostic parameter that could help to identify potentially progressive lesions. However, the diagnostic and therapeutic implications of telomerase activation need to be clarified in clinical trials. Int. J. Cancer (Pred. Oncol.) 84:426–431, 1999. © 1999 Wiley‐Liss, Inc.

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Telomerase Activity and Survival of Patients With Node-Positive Breast Cancer

Abstract: Telomerase activity in human breast cancers is associated with a more aggressive tumor phenotype in patients.

Cited by 125 publications

References 36 publications

Telomerase activity in ductal carcinoma in situ and invasive breast cancer

Telomerase activity in ductal carcinoma in situ and invasive breast cancer

KOC is a novel molecular indicator of malignancy

Differential telomerase activity, expression of the telomerase catalytic sub-unit and telomerase-RNA in ovarian tumors

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