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

Oncogene amplification, such as HER-2/neu (C-erbB-2), is a manifestation of genetic instability often associated with the genesis and progression of cancer, including cervical cancer. Oncogene overexpression is traditionally studied using immunohistochemistry. We previously reported studies of oncogene amplification in breast cancer using fluorescent in situ hybridization (FISH), where the data support the hypothesis that HER-2/neu is a prognostic marker of poor outcome. To explore further the possible significance of HER-2/neu oncogene amplification in cervical cancer, we conducted a pilot study of 24 cervical cancer cases. The HER-2/neu FISH probe (Vysis, Inc., Downers Grove, IL) was used to measure gene amplification, with a chromosome 17 centromeric probe as an internal control. Out of 24 cases studied, 23 were informative. Of the 23 informative cases, 2 (8.7%) were found to be amplified. The rest (21 out of 23 or 91.3%) were nonamplified. Both amplified cases were invasive adenocarcinoma. Although the sample size of this pilot study may be somewhat small, the data obtained so far clearly demonstrated that detection of oncogene amplification in cervical cancer is not only feasible but is very sensitive, and suggest that further exploration using a larger sample size may be warranted.
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PMID:HER-2/neu oncogene amplification in cervical cancer studied by fluorescent in situ hybridization. 1046 75

Unbalanced chromosome translocations with breakpoints around 8p12, resulting in loss of distal 8p, are common in carcinomas. We have mapped the 8p12 breakpoints in three breast cancer cell lines, T-47D, MDA-MB-361, and ZR-75-1, using YACs and PACs between D8S540 and D8S255 by fluorescence in situ hybridization. All three lines had a breakpoint close to D8S505, proximal to HGL. Each breakpoint was distinct, but all were within 0.5 to 1.5 Mb of each other. The T-47D cell line had a straightforward translocation, but in MDA-MB-361 and ZR-75-1 the translocations were accompanied by local rearrangements of surprising complexity. Small regions of 8p from close to the breakpoint were duplicated or amplified as inserts in the attached chromosome fragment. ZR-75-1 also had retained a separate fragment of about 1 Mb, from the region 1 to 3 Mb telomeric to the common breakpoint, that included HGL. This line also had an interstitial deletion several megabases more centromeric. The data suggest that breakpoints on 8p12 are clustered in a small region and show that translocations breaking there may be accompanied by additional rearrangements.
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PMID:Chromosome translocations in breast cancer with breakpoints at 8p12. 1084

The inactive centromeres in neoplastic and transformed cells exhibit premature separation at prophase or pro-metaphase. The factor(s) that control this behavior are not known. Using a human breast cancer cell line, MDA 435, and a transformed mouse cell line (L929), we studied the relationship between the sequence of centromere separation and the replication of centromeric region associated with the active and inactive centromeres. Whereas the inactive centromeres in L929 cells replicate their pericentric heterochromatin earlier than that associated with the active centromeres, those in MDA 435 cells exhibited no strong correlation between early separation and replication. A comparison between the intragenomic patterns of separation with replication of only active centromeres showed that the former is not dependent upon the latter in either L929 cells or MDA 435 cells. These studies indicate that, whereas inactive centromeres in neoplastic cells separate prematurely in different species, there is no uniformity in the control for replication nor does the timing of separation depend upon the timing of replication of the centric region.
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PMID:Separation vs. replication of inactive and active centromeres in neoplastic cells. 1091 72

Translocation t(11;22)(q23;q11) is the most common constitutional reciprocal translocation in man. Balanced carriers are phenotypically normal, except for decreased fertility, an increased spontaneous abortion rate and a possible predisposition to breast cancer in some families. Here, we report the high resolution mapping of the t(11;22)(q23;q11) breakpoint. We have localised the breakpoint, by using fluorescence in situ hybidisation (FISH) walking, to a region between D11S1340 and WI-8564 on chromosome 11, and D22S134 and D22S264 on chromosome 22. We report the isolation of a bacterial artificial chromosome (BAC) clone spanning the breakpoint in 11q23. We have narrowed down the breakpoint to an 80-kb sequenced region on chromosome 11 and FISH analysis has revealed a variation of the breakpoint position between patients. In 22q11, we have sequenced two BACs (BAC2280L11 and BAC41C4) apparently mapping to the region; these contain low copy repeats (LCRs). Southern blot analysis with probes from BAC2280L11 has revealed different patterns between normal controls and translocation carriers, indicating that sequences similar/identical to these probes flank the translocation breakpoint. The occurrence of LCRs has previously been associated with genomic instability and "unclonable" regions. Hence, the presence of such repeats renders standard translocation breakpoint cloning techniques ineffective. Thus, we have used high resolution fiber-FISH to study this region in normal and translocation cases by using probes from 22q11, LCRs and 11q23. We demonstrate that the LCR containing the gap in 22q11 is probably substantially larger than the previous estimates of 100 kb. Using fiber-FISH, we have localised the breakpoint in 22q11 to approximately 20-40 kb from the centromeric border of the LCR (i.e. the telomeric end of AC006547) and have confirmed the breakpoint position on 11q23.
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PMID:Fine mapping of the constitutional translocation t(11;22)(q23;q11). 1091 80

To clarify the important role of the tumor-suppressor gene p53 in maintaining genetic integrity, we estimated chromosome instability and staining of overexpressed p53 protein in the same cells of five primary breast carcinomas. The method included both fluorescence immunohistochemistry and fluorescence in situ hybridization (FISH) on sections from formalin-fixed, paraffin-embedded breast cancer tissue. By using a centromeric FISH probe for chromosome 17 on interphase cells in these sections, we showed that cells with abnormal p53 protein expression had a statistically significant higher number of chromosome 17 than did cells with no p53 protein staining in the same samples as well as cells in four other tumor samples with no p53 protein staining. The samples identified positive for p53 abnormality by immunostaining were shown to have p53 mutation by constant denaturing gel electrophoresis analysis and DNA sequencing. These mutated samples were characterized by high DNA index, high S-phase, abnormal karyotype, and aneuploidy. The results strongly implicate p53 mutation as a cause for chromosomal instability and a crucial step in mammary carcinogenesis.
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PMID:p53 abnormality and chromosomal instability in the same breast tumor cells. 1106 99

Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence. Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plateau (termed selection or M0; refs 3-5), from which proliferative cells emerge to undergo further population doublings (approximately 20-70), before entering a second growth plateau (previously termed senescence or M1; refs 4-6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.
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PMID:Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. 1121 24

Normal cells in culture divide a certain amount of times and undergo a process termed replicative senescence. Telomere loss is thought to control entry into senescence. Activation of telomerase in tumors bypasses cellular senescence and is thus a requirement for tumor progression. We reported previously the preferential incorporation of 3'-azido-2', 3'-dideoxythymidine (AZT) in telomeric sequences of immortalized cells in culture. In this work, we have investigated the effects of chronic in vitro AZT exposure on F3II mouse mammary carcinoma cells. We demonstrate, for the first time, that AZT-treated tumor cells have a reduced tumorigenicity in syngeneic BALB/c mice. Tumor incidence was reduced and survival was prolonged in animals inoculated with AZT-treated cells when comparing with control counterparts. The number and size of spontaneous metastases were also decreased in animals inoculated with AZT-treated cells. In addition, we present evidence of morphological and biochemical signs of senescence, as shown by the staining for senescence associated beta-galactosidase activity, and induction of programmed cell death, as demonstrated by an increase of caspase-3 activity, in tumor cells exposed to AZT. These data indicate that chronic exposure of mammary carcinoma cells to AZT may be sufficient to induce a senescent phenotype and to reduce tumorigenicity.
Breast Cancer Res Treat 2001 Jan
PMID:Chronic in vitro exposure to 3'-azido-2', 3'-dideoxythymidine induces senescence and apoptosis and reduces tumorigenicity of metastatic mouse mammary tumor cells. 1126 35

Frequent allelic deletions at chromosome 11q24-q25 have been described in both early and late onset breast cancers, suggesting the existence of a gene locus implicated in the initiation and/or progression of the disease. In the present study we fine mapped this region further by loss of heterozygosity (LOH) analysis in a population of early onset breast cancer cases (n = 102, 22 to 36 years old). Loss of chromosomal material was assessed for possible association with patient survival as well as Nottingham histologic grade (NHG). Additionally, we investigated the involvement of the 11q24-q25 locus in a group of familial breast cancer cases with no detectable BRCA1 or BRCA2 gene alterations (n = 32, ages 28 to 40 years). Among the consecutive patients, extensive LOH was observed for all markers at 11q24-q25, with frequencies ranging from 42% to 54%. Deletion at the D11S4125 marker was found to be associated with reduced survival (p = 0.026), whereas the adjacent D11S387 marker correlated with higher histologic grade (p = 0.042). In the familial cases, the most telomeric markers showed substantially lower proportions of LOH, ranging from 10% to 21%. Comparison of the two patient groups demonstrated that this difference in LOH frequency was statistically significant for the D11S4098, D11S968, D11S387 and D11S4125 markers (p = 0.020, p = 0.029, p = 0.0070 and p = 0.0030, respectively). We conclude that 11q25 may harbor a gene implicated in early onset breast cancer. Our data suggest that the most probable position for this locus is defined by the markers D11S387 and D11S4125 and furthermore that it may play a less significant role in familial breast cancer cases not linked to either of the BRCA genes.
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PMID:Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer. 1129 Oct 47

Over-expression of a centrosomal serine/threonine kinase, STK15/BTAK, induces centrosome amplification, which results in chromosomal instability (CIN) in cell culture. In the present study, we investigated the correlation of STK15/BTAK mRNA expression with CIN and various clinicopathological factors in human breast cancer. STK15/BTAK mRNA levels were quantified by real-time PCR, and CIN values were determined by FISH analysis of chromosomes 1, 11 and 17 using centromeric probes. STK15/BTAK mRNA levels (0.310 +/- 0.413, mean +/- SD, n = 47) in breast cancers were significantly (p < 0.01) higher than those in normal breast tissues (0.044 +/- 0.029, n = 9). Furthermore, breast cancers were divided into 3 groups (low, intermediate and high) according to STK15/BTAK mRNA expression levels. CIN values of the low-expression group (27.9 +/- 12.6%, n = 18) were significantly (p < 0.01) higher than those of normal breast tissues (9.2 +/- 2.6%, n = 6), and those of the high-expression group (38.0 +/- 12.7%, n = 14) were significantly (p < 0.05) higher than those of the low-expression group. STK15/BTAK mRNA expression showed a significant (p < 0.05) correlation with high histological grade and negativity of estrogen and progesterone receptors. Our results demonstrate that STK15/BTAK mRNA is over-expressed in the majority of breast cancers and its over-expression is significantly associated with CIN, implicating STK15/BTAK in carcinogenesis through induction of CIN. STK15/BTAK mRNA levels might be useful as an indicator of poor prognosis and resistance to endocrine therapy.
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PMID:Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. 1129 Oct 73

The ribonucleoprotein telomerase synthesizes telomeric DNA by copying an intrinsic RNA template. In most cancer cells, telomerase is highly activated. Here we report a telomerase-based antitumor strategy: expression of mutant-template telomerase RNAs in human cancer cells. We expressed mutant-template human telomerase RNAs in prostate (LNCaP) and breast (MCF-7) cancer cell lines. Even a low threshold level of expression of telomerase RNA gene constructs containing various mutant templates, but not the control wild-type template, decreased cellular viability and increased apoptosis. This occurred despite the retention of normal levels of the endogenous wild-type telomerase RNA and endogenous wild-type telomerase activity and unaltered stable telomere lengths. In vivo tumor xenografts of a breast cancer cell line expressing a mutant-template telomerase RNA also had decreased growth rates. Therefore, mutant-template telomerase RNAs exert a strongly dominant-negative effect on cell proliferation and tumor growth. These results support the potential use of mutant-template telomerase RNA expression as an antineoplastic strategy.
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PMID:A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. 1143 16


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