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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent observations support the notion that telomerase expression is essential for the formation of human tumor cells [W-C. Hahn et al., Nature (Lond.), 400: 464-468, 1999]. The expression pattern of hTERT, the human telomerase catalytic subunit gene, is a rate-limiting determinant of the enzymatic activity of human telomerase. We have developed a real-time quantitative RT-PCR assay based on Taq-Man fluorescence methodology to quantify the full range of hTERT mRNA copy numbers. We validated the method on a series of 134 unilateral invasive primary breast cancer patients with known long-term outcome. Three-quarters of the breast tumors (75.4%; 101 of 134) were hTERT positive, i.e., contained detectable and quantifiable hTERT mRNA. hTERT-positive patients had significantly shorter relapse-free survival (P = 0.017) after surgery compared with hTERT-negative patients. The prognostic significance of hTERT status persisted in Cox multivariate regression analysis. When we subdivided hTERT-positive patients (n = 101) into three equal groups (tumors showing small, intermediate, or high increase in hTERT mRNA content), we observed statistical (or a trend toward) links between high hTERT mRNA levels and Scarff-Bloom-Richardson histopathological grade III (P = 0.066), and negative estrogen (P = 0.002) and progesterone (P = 0.048) receptor status, and therefore with higher aggressiveness of breast tumors. High hTERT mRNA levels were also linked to MYC gene overexpression (P = 0.007). These findings show that the quantitative evaluation of hTERT mRNA can have important prognostic significance in human breast cancer. In addition, our simple, rapid, and semiautomated assay method is suitable for routine hTERT mRNA detection and quantification and will be a powerful tool in large, randomized, prospective, cooperative group trials and in the hTERT-based therapy project.
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PMID:Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. 1069 May 23

The effects of retinoic acid (RA) and its analogs, all-trans RA, 9-cis RA and 13-cis RA, were investigated in human breast cancer MCF-7 cells and immortalized breast epithelial cell line MCF-10A. RA inhibited the telomerase activity of MCF-7 cells in a wide range of concentrations. RA at 10 microM also inhibited the growth of MCF-7 cells in a time-dependent manner. However, no significant growth inhibition was found between untreated control and RA-treated MCF-10A cells. Moreover, a marked inhibition of telomerase activity by RA was detected early in MCF-7 cells (after 24 h of RA treatment), which was preceded by a reduction of hTERT mRNA expression (after 12 h of RA treatment). However, MCF-10A cells showed a reduction of telomerase activity and down-regulation of hTERT after 4 days of RA treatment. Simultaneous changes in hTERT mRNA expression and telomerase activity were found for MCF-10A cells. The expressions of hTR and hTEP1 telomerase component genes were not changed after RA treatment. These results indicate that the anti-breast cancer activity of RA could be mediated by its ability to down-regulate the expression of hTERT telomerase gene.
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PMID:Inhibition of cell growth and telomerase activity of breast cancer cells in vitro by retinoic acids. 1102

Tumor-derived circulating DNA has been found in the plasma of cancer patients. Alterations include decreased strand stability, mutations of oncogenes or of tumor suppressor genes, microsatellite alterations, and hypermethylation of several genes. RNA has also been found circulating in the plasma of normal subjects and cancer patients. Tyrosinase mRNA has been extracted from the serum of melanoma patients and subjected to RT-PCR. Moreover, the presence of cell-free EBV-associated RNA has been reported in the plasma of patients with nasopharyngeal carcinoma. Human telomerase comprises two RNA subunits, telomerase RNA template (hTR) and its catalytic component, telomerase reverse transcriptase protein (hTERT). Expression of these subunits correlates with telomerase activity. Using RT-PCR, we investigated whether these RNA subunits were present in the serum of 18 patients with breast cancer, 2 patients with benign breast disease, and 21 normal subjects. The presence of amplifiable RNA was confirmed in all tissue and serum samples using RT-PCR of glyceraldehyde-3-phosphate dehydrogenase RNA. hTR was found in 17 of 18 tumors (94%) and 5 of 18 serum samples (28%). hTERT was also detected in 17 of 18 tumors (94%) and in 4 of 16 available serum samples (25%). hTR and hTERT were undetectable in tissues and sera taken from 2 patients with benign disease and in the sera of 21 normal subjects. We conclude that RNA is detectable in the serum of breast cancer patients and that tumor-derived mRNA can be extracted and amplified using RT-PCR, even in patients with localized disease. This may have implications for cancer diagnosis and follow-up in the future.
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PMID:Telomerase RNA as a detection marker in the serum of breast cancer patients. 1105 Dec 24

Because autocrine transforming growth factor beta (TGF-beta) can suppress carcinogenesis, which is often associated with telomerase activation, we studied whether autocrine TGF-beta inhibits telomerase activity. Restoration of autocrine TGF-beta activity in human colon carcinoma HCT116 cells after reexpression of its type II receptor (RII) led to a significant reduction of telomerase activity and the mRNA level of telomerase reverse transcriptase (hTERT), whereas suppression of the autocrine TGF-beta activity with a dominant negative RII without the cytoplasmic domain (deltaRII) in human breast cancer MCF-7 cells led to a significant increase of telomerase activity and hTERT mRNA level. This appears to be due to repression of hTERT mRNA transcription because exogenous TGF-beta treatment of MCF-7 cells transiently transfected with a hTERT promoter-reporter construct significantly repressed the hTERT promoter activity in a dose-dependent manner. Furthermore, the hTERT promoter activity was significantly decreased in HCT116 RII cells and increased in MCF-7 deltaRII cells when compared with their respective controls. Therefore, autocrine TGF-beta appears to target hTERT promoter to inhibit telomerase activity.
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PMID:Autocrine transforming growth factor beta suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells. 1124 66

A novel pentacyclic acridine, 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4), has been identified as a potent inhibitor of telomerase in the cell-free telomeric repeat amplification protocol (TRAP). Modeling and biophysical studies suggest that RHPS4 inhibits telomerase through stabilization of four-stranded G-quadruplex structures formed by single-stranded telomeric DNA. In contrast to G-quadruplex interactive telomerase inhibitors described previously, RHPS4 inhibited telomerase at submicromolar levels (50% inhibition in the TRAP assay at 0.33 +/- 0.13 microM). Moreover, RHPS4 exhibited a wide differential between this potent inhibition of telomerase and acute cellular cytotoxicity (mean IC(50) value of 7.02 microM in 4-day growth inhibition assay). RHPS4, when added to 21NT breast cancer cells at nonacute cytotoxic concentrations (200 nM) every 3 to 4 days, induced a marked cessation in cell growth after 15 days. Similar effects were observed using another cell line possessing relatively short telomeres, A431 human vulval carcinoma cells, but not in a human ovarian carcinoma cell line (SKOV-3) possessing relatively long telomeres. In 21NT cells, growth cessation was accompanied by an increase in cells in the G(2)/M phase of the cell cycle, a reduction in cellular telomerase activity, and a lower expression of the hTERT gene. These effects occurred in the absence of a detectable reduction in telomere length as measured by slot blotting. RHPS4 also induced a cessation of growth of GM847 cells that maintain telomeres by a nontelomerase alternative mechanism for lengthening telomeres (ALT) after 15 days. RHPS4 represents a promising G-quadruplex interactive small molecule that is a potent cell-free inhibitor of human telomerase and induces growth inhibitory effects in human tumor cell lines after prolonged (2-week) exposure to nonacute cytotoxic drug concentrations.
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PMID:Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. 1164 26

This paper reviews the Twenty-fourth Annual San Antonio Breast Cancer Symposium. The preliminary results of the ATAC study have shown that Arimidex is superior to tamoxifen in postmenopausal women with ER-positive early breast cancer in terms of DFS, adverse effects and prevention of contralateral breast cancer. However, longer follow up is required to assess the drug safety regarding bone mineral density and cognitive function. Letrozole seems to be superior to tamoxifen as a first-line therapy in ER-positive advanced breast cancer in postmenopausal women. Although the incidence of acute myeloid leukaemia is significantly increased (cumulative incidence at 5 years = 1.1%) in breast cancer patients receiving cyclophosphamide and anthracyclines, the risk of this complication is easily outweighed by the benefits of chemotherapy. Adjuvant clodronate was found to be associated with a significant reduction in the incidence of bone metastases during the treatment period. A randomised trial comparing axillary dissection and axillary radiotherapy (RT) for early breast cancer reported no significant difference in survival at 15 years. However, axillary recurrence was significantly increased in the RT group. hTERT protein expression by IHC was found to correlate significantly with breast cancer-specific survival. There is no evidence to support the use of IHC of the sentinel node in routine clinical practice. LCIS is currently considered as a non-obligate precursor to breast cancer rather than just a risk factor.
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PMID:Recent advances in breast cancer (the Twenty-fourth San Antonio Breast Cancer Symposium, December, 2001). 1199 42

Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence. Using a well characterized model system for breast cancer, we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in beta-galactosidase, a marker of senescence. Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents. Stable introduction of hTERT, the catalytic protein component of telomerase, into MCF-7 cells caused an increase in telomerase activity and telomere length. Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening, indicating that the senescence after treatment is telomere length-independent. However, we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres, showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype. To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening.
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PMID:Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. 1210 Nov 84

The inhibitory effect of curcumin, the yellow-colored pigment from turmeric, on telomerase activity was analyzed in human mammary epithelial (MCF-10A) and breast cancer (MCF-7) cells. Telomerase activity in MCF-7 cells is 6.9-fold higher than that of human mammary epithelial cells. In MCF-7 cells, telomerase activity decreased with increasing concentrations of curcumin, inhibiting about 93.4% activity at 100 microM concentration. The inhibition of telomerase activity in MCF-7 cells may be due to down-regulation of hTERT expression. Increasing concentrations of curcumin caused a steady decrease in the level of hTERT mRNA in MCF-7 cells whereas the level of hTER and c-myc mRNAs remained the same. Our results suggest that curcumin inhibits telomerase activity by down-regulating hTERT expression in breast cancer cells and this down-regulation is not through the c-myc pathway.
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PMID:Curcumin inhibits telomerase activity through human telomerase reverse transcritpase in MCF-7 breast cancer cell line. 1210 41

Steroid hormones have been implicated in the regulation of cellular proliferation and of telomerase activity. Because progestin modulates cell cycle progression in vitro, we investigated if the regulation of telomerase activity by progesterone could be cell cycle-dependent. We found that progesterone treatment of the T47D breast cancer cell line induced both the down-regulation of hTERT (human telomerase reverse transcriptase) mRNA expression and telomerase activity together with a cell cycle blockage characterized by a accumulation of cells in G0/G1-phase. For the first time, after the analysis of cells sorted by flow cytometry, we showed that telomerase activity is lower in the G0/G1-phase than in the S- or G2/M-phase, with or without hormone treatment. These results indicated that the hTERT gene is not a direct target of progesterone; after treatment the down-regulation of telomerase activity is mainly related to the accumulation of cells in the G0/G1-phase of the cell cycle.
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PMID:Down-regulation of telomerase activity after progesterone treatment of human breast cancer cells: essential role of the cell cycle status. 1217 98

Caveolin-1 (Cav-1) is the principal structural protein of caveolae membranes that are found in most cells types, including mammary epithelial cells. Recently, we mapped the human CAV1 gene to a suspected tumor suppressor locus (7q31.1/D7S522) that is deleted in a variety of human cancers, as well as mammary tumors. In addition, the CAV1 gene is mutated (P132L) in up to approximately 16% of human breast cancers. The mechanism by which deletion or mutation of the Cav-1 gene contributes to mammary tumorigenesis remains unknown. To understand the role of the Cav-1 (P132L) mutation in the pathogenesis of human breast cancers, we generated the same mutation in wild-type (WT) Cav-1 and studied its behavior in cultured cells. Interestingly, the P132L mutation leads to formation of misfolded Cav-1 oligomers that are retained within the Golgi complex and are not targeted to caveolae or the plasma membrane. To examine whether the Cav-1 (P132L) mutant behaves in a dominant-negative manner, we next co-transfected cells with Cav-1 (P132L) and WT Cav-1, and evaluated their caveolar targeting. Our results indicate that Cav-1 (P132L) behaves in a dominant-negative manner, causing the mislocalization and intracellular retention of WT Cav-1. Virtually identical results were obtained when Cav-1 (P132L) was stably expressed at physiological levels in a nontransformed human mammary epithelial cell line (hTERT-HME1). These data provide a molecular explanation for why only a single mutated CAV1 allele is found in patients with breast cancer. Thus, we next investigated if functional inactivation of Cav-1 gene expression leads to mammary tumorigenesis in vivo. For this purpose, we performed mammary gland analysis on Cav-1-deficient mice (-/-) that harbor a targeted disruption of the Cav-1 gene (a null mutation). Interestingly, we show that inactivation of Cav-1 gene expression leads to mammary epithelial cell hyperplasia, even in 6-week-old virgin female mice. These data clearly implicate loss of functional Cav-1 in the pathogenesis of mammary epithelial cell hyperplasia, and suggest that Cav-1-null mice represent a novel animal model to study premalignant mammary disease.
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PMID:Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia. 1236 9


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