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

The cell cycle regulatory gene cyclin D1 is a candidate oncogene in breast cancer. It is overexpressed in 30-50% of invasive primary breast cancers and plays a key role in mediating mitogenic responses to steroids and growth factors in breast cancer cells in vitro. Because the role of cyclin D1 in the proliferative and early noninvasive stages of breast cancer is largely unknown, we examined normal breast epithelium (NBE), proliferative disease (PD), ductal carcinoma in situ (DCIS), and invasive carcinoma (IC) to evaluate the timing and possible importance of cyclin D1 expression in the development of breast cancer. Using immunohistochemistry, we examined cyclin D1 protein expression in 471 breast tissue samples. A quantitative scoring system for immunohistochemistry based on percentage of positive cells was developed that correlated with Western blot analysis of antigen concentration in paired samples (r2 = 0.91, P = 0.003). A sample was considered positive if >5% of relevant epithelial cells demonstrated nuclear staining. Cyclin D1 positivity was observed in 11.7% (7 of 60) samples of NBE, 25% (11 of 44) of PD without atypia, 39.4% (13 of 33) of atypical ductal hyperplasia, 43.6% (17 of 39) of low-grade DCIS, 47.9% (23 of 48) of high-grade DCIS, and 48.3% (99 of 205) of IC. Cyclin D1 expression was significantly higher in PD than NBE (P = 0.006) and in DCIS than PD (P = 0.038). There was no significant increase from DCIS to IC (P = 0.52). The increase in cyclin D1 expression in the overall progression from NBE to IC was also highly significant (P = 0.0001). Therefore, cyclin D1 expression was detected at levels significantly greater than in NBE in the earliest proliferative epithelial lesions of the breast with a further significant increase accompanying the progression to any form of cancer. This suggests that overexpression of cyclin D1 protein is important at the earliest stages of breast oncogenesis and continues to have a crucial role throughout the development of malignancy.
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PMID:Cyclin D1 protein is overexpressed in hyperplasia and intraductal carcinoma of the breast. 956 77

The cyclin D1/CCND1 oncogene (PRAD1) is amplified in 15% of primary human breast cancers and overexpressed in 30-50% of breast cancers, suggesting that mechanisms in addition to DNA amplification may lead to deregulated expression of this gene in breast cancer. Cyclin D1 overexpression at a higher frequency than gene amplification is also seen in a variety of other tumors. Cyclin D1 overexpression without amplification could result from a trans-acting regulatory disturbance or could be a consequence of a clonal regulatory mutation in one allele of the gene. We have, therefore, examined whether the overexpression of cyclin D1 mRNA is derived from one parental allele or both alleles in tumor cell lines with or without amplification of the cyclin D1 gene. Eight tumor cell lines, MCF-7, SK-BR-3, ZR-75-1, U-2-OS, SK-LMS-1, DLD1, HCT15, and HT29, out of 20 tumor cells initially examined were found to be heterozygous at the polymorphic NciI site within exon 4 of the cyclin D1 gene. Polymerase chain reaction and NciI digestion (PCR-RFLP) analysis of genomic DNA demonstrated DNA amplification of one allele in the ZR-75-1 cells and HT29 cells and no such imbalance in cyclin D1 gene copy number in the other cells, consistent with Southern blot analyses. Reverse-transcription polymerase chain reaction analysis and NciI digestion (RT-PCR-RFLP) of total cDNA revealed that the overexpressed cyclin D1 mRNA is preferentially derived from the amplified allele in the ZR-75-1 and HT29 cells. In contrast, the other tumor cells overexpressed cyclin D1 mRNA equally from both alleles. This finding strongly suggests that, in breast, sarcoma, and in colon cancer cells with cyclin D1 overexpression and normal gene copy number, elevated levels of cyclin D1 mRNA result from a trans-acting influence on both alleles rather than a clonal somatic mutation or rearrangement in or near a single cyclin D1 gene.
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PMID:Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression. 959 36

The effects of immunosuppressants and inhibitors of specific calcium/calmodulin kinase (CaMK) of types II and IV on progestin/glucocorticosteroid-induced transcription were studied in two human stably transfected breast cancer T47D cell lines. The lines contain the chloramphenicol acetyl transferase (CAT) gene under control either of the mouse mammary tumor virus promoter (T47D-MMTV-CAT), or the minimal promoter containing five glucocorticosteroid/progestin hormone response elements [T47D-(GRE)5-CAT]. Progestin- and triamcinolone acetonide (TA)-induced CAT gene expression was inhibited in a dose-dependent manner in both lines by preincubation with rapamycin (Rap) and, to a lesser extent, with FK506, but not with cyclosporin A. CaMK II and/or IV inhibitors KN62 and KN93 also inhibited progestin- and TA-stimulated transcription in both lines. None of these drugs had any effect on basal transcription. The antagonist RU486 inhibited all the effects of both progestin and TA, suggesting that progesterone receptor (PR)-, as well as glucocorticosteroid receptor (GR)- mediated transactivation are targets of immunosuppressants and CaMKs in T47D cells. Indeed, Northern analysis showed that Rap, KN62, and, to a lesser degree, FK506 inhibited progestin stimulation of Cyclin D1 mRNA levels, but not those of the non-steroid-regulated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Addition of Rap or KN62 after exposure of cells to progesterone agonist Org 2058 had no effect on induction of CAT activity. Taken together, these data indicate that Rap and FK506, as well as CaMK inhibitors, inhibit steroid-induced activities of exogenous, as well as of some endogenous, steroid receptor-regulated genes by a mechanism preceding hormone-induced receptor activation. Rap appeared to stabilize a 9S form of [3H]Org 2058-PR complexes isolated from T47D (GRE)5CAT cell nuclei. By contrast, the progesterone receptor (PR) was isolated from cells treated with KN62 as a 5S entity, undistinguishable from the 5S PR species extracted from cells treated with progestin only. The nuclear 9S-[3H]Org2058-PR resulting from cells exposed to Rap, contained, in addition to the heat shock proteins of 90 kDa and 70 kDa (hsp90 and hsp70), the FK506-binding immunophilin FKBP52 but not FKBP51, although the latter was part of unliganded PR heterocomplex associated with hsp90. These results suggest that Rap and KN62 act upon the PR by distinct mechanisms, with only Rap impeding progestin-induced PR transformation. FKBP51 appeared to dissociate from the receptor heterocomplex, but not from hsp90, after hormone binding to PR in vitro and in vivo, whether in the presence or not of Rap and KN62. Immunoprecipitation experiments distinguished two PR- and glucocorticosteroid (GR)-associated molecular chaperone complexes, containing hsp90 and hsp70 and FKBP52 or FKBP51. Another complex identified in T47D cytosol contained hsp90 and the cyclosporin A-binding cyclophilin of 40 kDa, CYP40, but not hsp70, PR, or GR. These observations support the concept that FKBP51 and FKBP52 can act as regulators of Rap and FK506 activity upon PR and GR-mediated transcription, a mechanism that could be also regulated by type II and/or type IV CaMKs.
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PMID:Calcium/calmodulin kinase inhibitors and immunosuppressant macrolides rapamycin and FK506 inhibit progestin- and glucocorticosteroid receptor-mediated transcription in human breast cancer T47D cells. 965 3

Experimental studies suggest that cyclin D1 is a potential oncogene but in clinical studies of invasive breast cancer, overexpression of cyclin D1 is found to be associated with oestrogen receptor (ER) expression and low histological grade, both markers of good prognosis. Immunohistochemistry has been used to examine the relationship between cyclin D1 expression and differentiation in 36 cases of ductal carcinoma in situ (DCIS) and the interrelationship between expression of cyclin D1, its associated protein product of the retinoblastoma gene (pRb), and ER, in this group of cases. The expression of these markers has also been examined in nine cases of atypical ductal hyperplasia (ADH) and these results have been compared with the levels of expression seen in DCIS. Cyclin D1 overexpression was found in 23/36 (64 per cent) cases of DCIS and, in contrast to invasive carcinoma, there was no relationship with either differentiation or ER expression. The level of pRb expression was significantly associated with cyclin D1 expression (rS = 0.49, P = 0.001) and only two cases (6 per cent) were pRb-negative. There was no association between pRb and differentiation of DCIS or ER status. In contrast to DCIS, only one case of ADH showed overexpression of cyclin D1 (Mann-Whitney U-test, P = 0.02). All cases of ADH were ER-positive and showed moderate pRb staining, similar to that seen in well-differentiated DCIS. These results provide further evidence that overexpression of cyclin D1 plays a role early in carcinogenesis.
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PMID:Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. 966 5

The evolution of somatic genetic aberrations in breast cancer has remained poorly understood. The most common chromosomal abnormality is hyperdiploidy, which is thought to arise via a transient hypodiploid state. However, hypodiploidy persists in 1 to 2% of breast tumors, which are characterized by a poor prognosis. We studied the genetic aberrations in 15 flow cytometrically hypodiploid breast cancers by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). Surprisingly, numerous copy number gains were detected in addition to the copy number losses. The number of gains per tumor was 4.3 +/- 3.2 and that of losses was 4.5 +/- 3.3 (mean +/- SD), which is similar to that previously observed in hyperdiploid breast cancers. Gains at chromosomes or chromosomal regions at 11q13, 1q, 19, and 16p and losses of 2q, 4, 6q, 9p, 13, and 18 were most commonly observed. Compared with unselected breast carcinomas, hypodiploid tumors showed certain differences. Loss of chromosome 4 (53%) and gain of 11q13 (60%) were significantly more common in hypodiploid tumors. The gain at 11q13 was found by FISH to harbor amplification of the Cyclin D1 oncogene, which is therefore three to four times more common in hypodiploid than in unselected breast cancers (15 to 20%). Structural chromosomal aberrations (such as Cyclin D1 amplification) were present both in diploid and hypodiploid tumor cell populations, as assessed by FISH and CGH after flow cytometric sorting. Together these results indicate that hypodiploid tumors form a distinct genetic entity of invasive breast cancer, although they probably share a common genetic evolution pathway where structural chromosomal aberrations precede gross DNA ploidy changes.
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PMID:Genetic aberrations in hypodiploid breast cancer: frequent loss of chromosome 4 and amplification of cyclin D1 oncogene. 966 80

1,25(OH)2D3 is a known growth inhibitor and differentiation inducer of several cancer cell lines. To establish the molecular mechanism of 1,25(OH)2D3 as an antiproliferating agent, its effect on proliferation and gene regulation was studied in human breast cancer MCF-7 cells. 1,25(OH)2D3 inhibited cell proliferation dose dependently through G1 arrest. Cyclin D1 transcription levels decreased rapidly in 1,25(OH)2D3-treated cells while protein levels only decreased after 72 h of treatment. Transcription levels of p21 and p27 were upregulated with chronologically consistent changes in cell cycle distribution. Experiments with TGF-beta neutralising antibodies revealed that the largest effect of 1,25(OH)2D3 on cell proliferation is likely due to a TGF-beta independent mechanism of action. The cell cycle regulatory genes, cyclin D1 and p27, are probably involved herein as their expression was not affected by the presence of neutralising antibodies. However, upregulation of p21 was completely abrogated. Therefore, the TGF-beta signalling pathway is thought to be responsible for p21 upregulation.
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PMID:Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells. 978 3

Cyclin D1 plays a critical role in regulating cell-cycle progression. Gene amplification and protein overexpression of cyclin D1 have been detected in breast cancer but little is known concerning whether these changes occur in normal breast tissue and in breast lesions associated with increased risk of development of invasive breast cancer. We looked for cyclin D1 gene amplification and protein overexpression in 30 cases of benign breast disease (16 epithelial hyperplasias without atypia and 14 atypical ductal hyperplasias) and 18 ductal carcinomas in situ by use of differential PCR and immunohistochemical staining. We compared the resulting frequencies to those in 15 cases of normal breast tissue and 17 invasive ductal carcinomas. We found cyclin D1 gene amplification in 15% of those with normal breast tissue, 19% of those with epithelial hyperplasia without atypia, 27% of those with atypical ductal hyperplasia, 35% of those with ductal carcinoma in situ, and 25% of those with invasive ductal carcinoma; corresponding figures for protein overexpression were 13, 13, 57, 50, and 64%. These results suggest that cyclin D1 amplification and protein overexpression can occur before histologic alterations are seen but that the frequencies of these changes are higher in histologic lesions with cellular atypia (atypical hyperplasia and ductal carcinoma in situ), reaching frequencies similar to those observed in invasive carcinoma.
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PMID:Cyclin D1 gene amplification and protein expression in benign breast disease and breast carcinoma. 983 Dec 6

The estrogen receptor (ER) is an important regulator of growth and differentiation of breast epithelium. Transactivation by ER depends on a leucine-rich motif, which constitutes a ligand-regulated binding site for steroid receptor coactivators (SRCs). Cyclin D1 is frequently amplified in breast cancer and can activate ER through direct binding. We show here that cyclin D1 also interacts in a ligand-independent fashion with coactivators of the SRC-1 family through a motif that resembles the leucine-rich coactivator binding motif of nuclear receptors. By acting as a bridging factor between ER and SRCs, cyclin D1 can recruit SRC-family coactivators to ER in the absence of ligand. A cyclin D1 mutant that binds to ER but fails to recruit coactivators preferentially interferes with ER activation in breast cancer cells that have high levels of cyclin D1. These data support that cyclin D1 contributes significantly to ER activation in breast cancers in which the protein is overexpressed. Our present results reveal a novel route of coactivator recruitment to ER and establish a direct role for cyclin D1 in regulation of transcription.
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PMID:Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. 983 2

Expression of proliferation- and apoptosis-related proteins was studied by immunohistochemistry in 130 usual ductal hyperplasias of the breast, of which 39 cases (30%) had adjacent invasive cancer. Overexpression of cyclin D1 and Ki-67 was found in 6% and 29% of the cases, respectively. Only two mild ductal hyperplasias were Her-2/neu positive. Overexpression of p21 and reduced expression of p27, both cdk-inhibitors, was seen in 16% and 27% of the lesions, respectively. Reduced expression of bcl-2 was found in 16% of the cases, and p53 accumulation was present in 8%. Expression of six of the seven studied proteins showed no significant difference between mild, moderate, or florid ductal hyperplasias, indicating that there are no important cell biological differences with regard to the studied proteins between the lesions within this morphologically continuous spectrum. In addition, there were no differences between lesions with and without an invasive component. Cyclin D1 positivity was exclusively seen in lesions with 75% or more p27-positive nuclei. No significant correlations were found between other proteins. Twenty-three of 91 lesions (25%) had multiple events, of which five showed altered expressions of three or four proteins. In conclusion, altered protein expression of several proliferation- and apoptosis-related genes that are known to be involved in invasive breast cancer also may be found in usual ductal hyperplastic lesions, including several lesions with multiple events. This implies that usual ductal hyperplastic lesions may be among the earliest lesions within the breast oncogenetic spectrum.
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PMID:Expression of proliferation and apoptosis-related proteins in usual ductal hyperplasia of the breast. 986 45

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.
Breast Cancer Res Treat 1998
PMID:Cyclin D1 in breast cancer. 1006 68


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