Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Programmed cell death (apoptosis) is a normal physiological process, which could in principle be manipulated to play an important role in cancer therapy. The key importance of p53 expression in the apoptotic response to DNA-damaging agents has been stressed because mutant or deleted p53 is so common in most kinds of cancer. An important strategy, therefore, is to find ways to induce apoptosis in the absence of wild-type p53. In this paper, we compare apoptosis in normal human mammary epithelial cells, in cells immortalized with human papilloma virus (HPV), and in mammary carcinoma cell lines expressing wild-type p53, mutant p53, or no p53 protein. Apoptosis was induced with mitomycin C (MMC), a DNA cross-linking and damaging agent, or with staurosporine (SSP), a protein kinase inhibitor. The normal and HPV-transfected cells responded more strongly to SSP than did the tumor cells. After exposure to MMC, cells expressing wild-type p53 underwent extensive apoptosis, whereas cells carrying mutated p53 responded weakly. Primary breast cancer cell lines null for p53 protein were resistant to MMC. In contrast, two HPV immortalized cell lines in which p53 protein was destroyed by E6-modulated ubiquitinylation were highly sensitive to apoptosis induced by MMC. Neither p53 mRNA nor protein was induced in the HPV immortalized cells after MMC treatment, although p53 protein was elevated by MMC in cells with wild-type p53. Importantly, MMC induced p21 mRNA but not p21 protein expression in the HPV immortalized cells. Thus, HPV 16E6 can sensitize mammary epithelial cells to MMC-induced apoptosis via a p53- and p21-independent pathway. We propose that the HPV 16E6 protein modulates ubiquitin-mediated degradation not only of p53 but also of p21 and perhaps other proteins involved in apoptosis.
 ...
PMID:The human papilloma virus 16E6 gene sensitizes human mammary epithelial cells to apoptosis induced by DNA damage. 764

Cytogenetic and molecular analyses of human breast cancer cells have identified consistent losses of specific chromosomal regions in these tumors, suggesting that such regions harbor tumor suppressor genes whose homozygous loss or inactivation directly contributes to tumorigenesis. To date, deletions of chromosome 8 sequences have been described infrequently and only in low percentages of breast carcinomas. We report the identification of a new DNA marker on chromosome 8p that is deleted in 6 (75%) of 8 breast carcinoma cell lines and in 1 primary breast carcinoma examined. No deletion of this marker was detected in any normal or nonbreast carcinoma cell lines analyzed. Southern blot and fluorescence in situ hybridization studies indicate that this clone maps to chromosome 8 between bands p12 and p21. These observations suggest that a new gene, whose loss or inactivation may foster breast carcinoma tumorigenesis, may reside in this chromosome 8p region.
 ...
PMID:Loss of chromosome 8p sequences in human breast carcinoma cell lines. 807 45

Primary breast tumors were tested for loss of heterozygosity (LOH), on chromosome 9p with microsatellite markers restricted to a 28 cM region including the MTS1 gene. LOH was found with at least 1 marker in 38% of the 201 cases analyzed. A high frequency of deletions was detected at the 9p23-p21 region, indicating a tumor suppressor gene(s) important for breast cancer tumorigenesis. Tumors with and without LOH on 9p were compared with respect to clinico-pathological factors using chi 2 analysis. Tumors with 9p LOH were significantly associated with high S-phase status and aneuploidy, but not with type, node status, estrogen and progesterone receptor content or age of the patients at diagnosis. Survival analysis showed that LOH at 9p did not significantly affect the survival rate of breast cancer patients. Our results indicate that the aberrations on 9p detected in this study are not of independent prognostic value. A significant association was found between LOH at 9p and LOH at chromosomal arms 3p and 6q, which is an additional contribution toward understanding the genetic events in breast tumor pathogenesis.
 ...
PMID:Loss of heterozygosity on chromosome 9 in human breast cancer: association with clinical variables and genetic changes at other chromosome regions. 855 Feb 38

Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.
 ...
PMID:Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. 870 May 12

Chromosome 3p deletions in breast cancer have been detected at 3p12-p21 by cytogenetic and loss of heterozygosity studies. Recently, we have cloned the FHIT (fragile histidine triad) gene, located at 3p14.2. Abnormalities of the FHIT locus were found in many established cancer cell lines, and the gene was abnormally transcribed in primary tumors of the digestive tract and lung. In this report, we describe the analysis of breast cancer, cell lines, and primary tumors for alterations in transcription of the FHIT gene; about 20% of the samples exhibited altered transcripts. In most of the cases, aberrant transcripts were missing exons. Lack of expression of FHIT mRNA was observed in another 10% of primary tumor samples. These results suggest that alterations in the FHIT gene may play an important role in breast cancer tumorigenesis and suggest that the MIT gene product functions in the control of the tumorigenic phenotype in a large variety of human neoplasms.
 ...
PMID:The FHIT gene at 3p14.2 is abnormal in breast carcinomas. 876 1

Detailed physical maps of the human genome are important resources for the identification and isolation of disease genes and for studying the structure and function of the genome. To improve the definition of the 8p12-p21 chromosomal region, an integrated physical and genetic map was constructed extending from the genes. NEFL to FGFR1. The map comprises a series of contigs (the larger of these being around 9 Mb) of yeast artificial chromosomes (YACs) spanning the proximal region of deletion involved in a broad range of human cancers, including breast carcinomas, and in the Werner syndrome. In addition, losses of heterozygosity at 8p markers and linkage analysis of breast cancer families were also detailed. Finally, several genes potentially involved in 8p-associated diseases, namely GTF2E2, PPP2CB, and HGL, were precisely mapped within the YAC contigs. The reported map and contigs of YACs should facilitate the search for putative genes involved in sporadic and familial breast cancer as well as in the Werner syndrome.
 ...
PMID:Integrated map of the chromosome 8p12-p21 region, a region involved in human cancers and Werner syndrome. 878 18

A yeast artificial chromosome (YAC), P1, and cosmid clone contig was constructed for the Werner syndrome (WRN) region of chromosome 8p12-p21 and used to clone a candidate gene for WRN. This region also possibly contains a familial breast cancer locus. The contig was initiated by isolating YACs for the glutathione reductase (GSR) gene and extended in either direction by walking techniques. Sequence-tagged site (STS) markers were generated from subclones of 2 GSR YACs and used to identify P1 and cosmid clones. Additional STSs were generated from P1 and cosmid clones and from potential expressed sequences identified by cDNA selection and exon amplification methods. The final contig was assembled by typing 17 YACs, 20 P1 clones, and 109 cosmids for 54 STS markers. The WRN region could be spanned by 2 nonchimeric YACs covering approximately 1.4 Mb. A P1/cosmid contig was established covering the core 700-800 kb of the WRN region. Fifteen new short tandem repeat polymorphisms and 2 biallelic polymorphic markers were identified and included as STSs in the contig. Analysis of these markers in Werner syndrome subjects demonstrates that the candidate WRN gene is in a region of linkage disequilibrium.
 ...
PMID:A YAC, P1, and cosmid contig and 17 new polymorphic markers for the Werner syndrome region at 8p12-p21. 881 76

In this study we report 11 cases with chromosome abnormalities involving 3p21. Nine cases were diagnosed as myelodysplastic syndrome (MDS), and two as acute myeloid leukemia (AML). Six of nine MDS cases were secondary to a primary malignant disease. In two patients, AML was secondary to breast cancer and polycythemia vera (PV). Seven of eleven patients had a history of intensive polychemotherapy and/or radiation therapy for 3.5 to 5 years. The mean interval from initial therapy to secondary disease was 13.2 years. Complex chromosomal aberrations were found in all 11 cases. Band 3p21 was involved in translocations in 9 patients and in deletions in 2 patients. A t(3;16)(p21;p13) was found in two cases. Additional abnormalities frequently included a -5, -7, as well as deletions or rearrangements of these 2 chromosomes. Data reported in this paper suggest that 3p21 is a recurrent treatment-related breakpoint in MDS and AML and is likely to contain a gene involved in the pathogenesis of this disease.
 ...
PMID:3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia. 897 89

Progestin antagonists inhibit the proliferation of progesterone receptor-positive cells, including breast cancer cells, by G1 phase-specific actions, but the molecular targets involved are not defined. Reduced phosphorylation of pRB, a substrate for G1 cyclin-dependent kinases (CDKs) in vivo, was apparent after 9 h treatment of T-47D breast cancer cells with the antiprogestins RU 486 or ORG 31710, accompanying changes in S phase fraction. Although the abundance of cyclin D1, Cdk4, and Cdk6 did not decrease cyclin D1-associated kinase activity was reduced by approximately 50% at 9-18 h. Similarly, cyclin E-associated kinase activity decreased by approximately 60% at 12-24 h in the absence of significant changes in the abundance of cyclin E and Cdk2. The CDK inhibitor p21 increased in mRNA and protein abundance and was present at increased levels in cyclin D1 and cyclin E complexes at times when their kinase activity was decreased. Increased p21 protein abundance was observed in another antiprogestin-sensitive cell line, BT 474, but not in two breast cancer cell lines insensitive to antiprogestins. These data suggest increased p21 abundance and concurrent inhibition of CDK activity as a mechanism for antiprogestin induction of growth arrest. Antiprogestin effects on proliferation were markedly reduced after ectopic expression of cyclin D1, indicating that inhibition of cyclin D1 function is a critical element in antiprogestin inhibition of proliferation. However, these data also implicate regulation of cyclin E function in antiprogestin regulation of cell cycle progression.
 ...
PMID:Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. 899 88

Cyclin-dependent kinase inhibitors (CKIs) p21, p27, p16, and p15 are an essential and integral part of cell cycle regulation. Studies on the expression of these inhibitors in normal versus tumor human breast cancer cells revealed that although p27 and p16 are expressed at higher levels in tumor cells, p21 and p15 expression were higher in normal cells. Analysis on the expression pattern of these proteins throughout the cell cycle in synchronized cells demonstrated a substantial increase in p21 during the S-phase in normal cells and barely detectable expression of p21 in any phase of the tumor cell cycle. Levels of p15, p16, and p27 remained relatively constant throughout the cell cycle of normal and tumor cells. Synchronization of tumor cells by lovastatin, which arrests cells in G1, resulted in increased levels of p21 and p27 with a concomitant decrease in cyclin-dependent kinase 2-associated kinase activity. Synchronization of cells by double-thymidine block did not result in the induction of p21 or p27. These observations suggest that lovastatin causes a profound cell cycle-independent alteration of CKI expression which is distinct from growth factor deprivation or thymidine block.
 ...
PMID:Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cells occurs in a cell cycle-independent fashion. 904 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>