Telomerase activity in relation to p53 status and clinico-pathological parameters in breast cancer

Roos, Göran; Nilsson, Pia; Cajander, Stefan; Nielsen, Niels Hilmer; Arnerlöv, Conny; Landberg, Göran

doi:10.1002/(sici)1097-0215(19980821)79:4<343::aid-ijc6>3.0.co;2-v

Cited by 50 publications

(29 citation statements)

References 18 publications

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“…These studies have reported conflicting results and most are limited to partial p53 analysis. [21][22][23][24][25] Thus, we undertook the present study to provide a detailed analysis of the p53 gene and evaluate its relationship with telomerase and its associated subunits hTR and hTERT in cell lines and patient derived ovarian cancers. The purpose of the current study was to test the hypothesis that p53 null tumors would be less likely to have telomerase activity.…”

Section: Resultsmentioning

confidence: 99%

p53 Null Mutations are Associated with a Telomerase Negative Phenotype in Ovarian Carcinoma

Sood¹,

Coffin

Jabbari

et al. 2002

Cancer Biology & Therapy

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© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n . ABSTRACTTelomerase activation and p53 dysfunction are important events in the development and progression of most cancers including ovarian cancer. However, many cancer cell lines and human tumors have been shown to lack telomerase, and maintain telomerase through the ALT (alternative lengthening of telomeres). It is not known whether specific types of p53 mutations are correlated with telomerase activity in human tumors. Invasive ovarian cancers (109) were analyzed for telomerase by ELISA and its subunits human telomerase RNA (hTR), and human telomerase reverse transcriptase (hTERT) by RT-PCR. p53 protein was analyzed in the same samples using immunohistochemistry, and p53 exons 2-11 were analyzed using SSCP and sequence analysis. Telomerase activity was detected in 80 (74%) of 109 tumors. The subunit hTR was consistently present in all ovarian cancer samples, and hTERT was expressed in 96 (88%) tumors. Thirteen (16%) tumors were negative for hTERT and none of these expressed telomerase. Fifty-seven (52%) tumors stained positive for p53, and there was no correlation with telomerase activity based on p53 staining (p = 0.08). Eighty-two (75%) tumors were found to have a p53 mutation, and 40 (36%) tumors contained a null mutation. Only 14% of the tumors with wild type or missense p53 were negative for telomerase activity. In contrast, 19 (48%) of 40 tumors with a p53 null mutation were negative for telomerase activity (p <0.001). There was no difference in the incidence of telomerase positivity between critical site versus non-critical site missense p53 mutations. Seventy-five percent of the tumors with a p53 mutation in the central region were telomerase positive. In contrast, only 47% of the tumors with a mutation in either the amino-or carboxy-terminus were telomerase positive (p = 0.03). Ovarian cancers with a p53 null mutation are more likely to lack telomerase activity. This may have implications for therapeutic approaches based on telomerase.

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Section: Resultsmentioning

confidence: 99%

p53 Null Mutations are Associated with a Telomerase Negative Phenotype in Ovarian Carcinoma

Sood¹,

Coffin

Jabbari

et al. 2002

Cancer Biology & Therapy

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“…Inactivation of p53 through speci®c interactions with oncogenic proteins, dephosphorylation or genetic mutations (Levine, 1997;Oren, 1998) is involved in cancer cell immortalization (Atadja et al, 1995;Bond et al, 1994;Rogan et al, 1995;Roos et al, 1998;Serrano et al, 1997;Wynford-Thomas, 1996). Similarly, activation of telomerase also plays an important role in tumor cell immortalization via preventing telomeres from shortening (Bodnar et al, 1998;de Lange, 1998;Greider, 1998;Harley et al, 1995;Kondo et al, 1998;Sedivy, 1998;Shay and Bacchetti, 1997), although there are scant data on the regulation of telomerase at molecular levels.…”

Section: Discussionmentioning

confidence: 99%

Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro

Cao

Berndt

et al. 1999

Oncogene

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“…The presence of nuclear pRb staining as an indicator of a functional gene product (detailed in Landberg and Roos, 1997) was monitored with the C15 antibody (Santa Cruz, CA, USA) and immunohistochemistry. SSCP analysis of exons 5 ± 8 in the p53 gene was performed to screen for p53 mutations as reported elsewhere (Roos et al, 1998). Telomerase activity was determined by the TRAP assay (Roos et al, 1998).…”

Section: Determination Of Cell Cycle and Other Aberrations In The Tummentioning

confidence: 99%

“…SSCP analysis of exons 5 ± 8 in the p53 gene was performed to screen for p53 mutations as reported elsewhere (Roos et al, 1998). Telomerase activity was determined by the TRAP assay (Roos et al, 1998).…”

Section: Determination Of Cell Cycle and Other Aberrations In The Tummentioning

confidence: 99%

Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors

et al. 2001

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The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controling cell cycle checkpoints, this type of aberrations could a ect tumor growth and survival thereby in¯uencing both tumor aggressiveness and potential response to treatments. We have previously identi®ed the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a di erentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly di erentiated tumors and higher stage. There was a signi®cantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway. Oncogene (2001) 20, 3497 ± 3505.

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Telomerase activity in relation to p53 status and clinico-pathological parameters in breast cancer

Cited by 50 publications

References 18 publications

p53 Null Mutations are Associated with a Telomerase Negative Phenotype in Ovarian Carcinoma

p53 Null Mutations are Associated with a Telomerase Negative Phenotype in Ovarian Carcinoma

Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro

Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors

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