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

The p73 gene is a structural and, in overexpression systems, functional p53 homologue. Ectopic p73 expression can activate a broad subset of p53-responsive genes, induce apoptosis, and act as a growth suppressor. Yet, viral oncoproteins that antagonize p53 (adenovirus E1B 55K, SV40 large T, and human papillomavirus E6) do not antagonize p73. This could suggest that inactivation of p73, in contrast to p53, is not required for tumorigenesis. Also, p73 is not activated by DNA damage. Because intragenic p73 mutations in tumors have not been reported and imprinting is idiosyncratic, tumor-specific changes in wild-type p73 expression levels become the most reliable guide toward identifying the normal function of p73 and its role in tumorigenesis. We analyzed 77 invasive breast cancers and 7 breast cancer cell lines for p73 mRNA expression levels, allelic origin, intragenic mutations, and COOH-terminal splice variants. A range of normal tissues, including breast, showed very low p73 expression, with little variation from tissue to tissue. In contrast, 38% (29 cases) of breast cancers had elevated p73 mRNA ranging from 5-25-fold above normal, with the remaining tumors (64%) falling within the normal range. Moreover, five of seven cell lines (71%) also exhibited p73 overexpression (13-73-fold). Yet, no correlation with p21 mRNA and protein levels was present, although four of the five lines were mutant for p53. Mutation analysis of the eight highest expressers showed wild type status. Eight of 14 informative samples were biallelic, whereas the remaining 6 samples showed monoallelic expression. Tumors and cell lines with p73 overexpression tended to exhibit a complex profile of up to six different COOH-terminal splice variants, whereas normal and transformed tissues with low p73 mRNA predominantly expressed p73 alpha. We confirm the previously described variants p73 gamma and delta in breast tissue and describe two novel isoforms, p73 epsilon and phi, thereby further enlarging combinatorial possibilities. Together, our in vivo data show that p73 does not have a role as a classic Knudson-type tumor suppressor in breast cancer.
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PMID:Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. 1039 74

An immunocytochemical assay for the p53-regulated protein product of the WAF1/Cip1 gene, p21(WAF1) (p21), was developed and applied to archival primary breast tumour material from 91 patients whose subsequent recurrent disease was treated with assessable courses of endocrine therapy. Nuclear localization of p21 protein was observed in 76 (82.4 per cent) cases. Status cut-offs were established and 29 (31.9 per cent) were deemed negative, 39 (42.9 per cent) weakly positive, and 23 (25.3 per cent) strongly positive. p21 status was inversely correlated with p53 protein (p=0.047) but did not relate to oestrogen receptor (ER) status, response to endocrine therapy, or time to further disease progression (TTP). Highly p21-positive patients had a significantly improved overall survival time (p=0. 020). Co-assessment of p21 and p53 subgroups revealed p21+/p53- patients to have good survival characteristics, whilst p21-/p53+ patients did poorly (p=0.008). The p21-/p53- patients overall did intermediately well, but Ki67-defined cellular proliferation analysis of these revealed two subclasses: those with high proliferation and poor survival times resembling the p21-/p53+ phenotype, and those with less proliferative tumours with good survival, similar to the p21+/p53- group. The significance of these results is discussed in the light of recent research concerning the role of p21 and p53 in breast cancer aetiology.
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PMID:p21(WAF1) expression and endocrine response in breast cancer. 1039 54

The effects of 24-hr exposures to 5-fluorouracil (FUra) and paclitaxel in various sequences were studied in MCF-7 breast cancer cells to determine an optimal schedule for possible clinical use. In clonogenic assays, pre-exposure to FUra followed by paclitaxel resulted in marked antagonism, while sequential paclitaxel followed by FUra was optimal. Concurrent or pre-exposure to paclitaxel did not affect [3H]FUra metabolism, [3H]FUra-RNA incorporation, or the extent of FUra-mediated thymidylate synthase inhibition. Paclitaxel led to G2/M phase accumulation that persisted for up to 24 hr after drug exposure, while a 24-hr FUra exposure produced S-phase accumulation. FUra pre-exposure diminished paclitaxel-associated G2/M phase block, whereas subsequent exposure to FUra after paclitaxel did not. FUra exposure resulted in transient induction of p53 and p21, which returned to basal levels 24 hr after drug removal. p53 and p21 protein content also increased markedly during paclitaxel exposure, accompanied by phosphorylation of Bcl-2. Double-stranded DNA fragmentation (approximately 50 kb) was seen at 48 hr when cells were exposed to paclitaxel for an initial 24-hr period. Paclitaxel-associated DNA fragmentation was not prevented by concurrent or subsequent exposure to FUra. Thus, paclitaxel-mediated G2/M phase arrest appeared to be a crucial step in induction of DNA fragmentation. Since an initial 24-hr paclitaxel exposure did not interfere with subsequent FUra metabolism or thymidylate synthase inhibition, and delayed exposure to FUra did not impede either paclitaxel-mediated induction of mitotic blockade or DNA fragmentation, the sequence of paclitaxel followed by FUra is recommended for clinical trials.
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PMID:Sequence-dependent antagonism between fluorouracil and paclitaxel in human breast cancer cells. 1042 68

Epidemiology suggests a possible relationship between exposure to power frequency magnetic fields (EMF) and breast cancer. One mechanism through which EMF could stimulate breast cancer induction is via altered expression of oncogenes and/or tumor suppressor genes that regulate normal and neoplastic growth. To evaluate the hypothesis that EMF action in the breast is mediated by alterations in gene expression, transcript levels of c-myc and a battery of other cancer-associated genes were quantitated in human breast epithelial cells exposed to pure, linearly polarized 60 Hz EMF with low harmonic distortion. HBL-100 cells and normal (non-transformed) human mammary epithelial cells were exposed to EMF flux densities of 0.1, 1.0 and 10.0 Gauss (G) for periods ranging from 20 min to 24 h; concurrent sham controls were exposed to ambient fields (<0.001 G) only. Gene expression was quantitated using ribonuclease protection assays. EMF exposure had no statistically significant effect on basal levels of c-myc transcripts in either human breast cell model, and had no effect on alterations in c-myc expression induced by 12-O-tetradecanoylphorbol-13-acetate. Transcript levels of c-erbB-2, p53, p21, GADD45, bax, bcl-x, mcl-1, and c-fos were also unaffected by EMF exposure. These results suggest that EMF is unlikely to influence breast cancer induction through a mechanism involving altered expression of these genes.
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PMID:Gene expression in human breast epithelial cells exposed to 60 Hz magnetic fields. 1042 19

The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer, suggesting the presence of a tumor suppressor gene(s) in this region. We identified a gene termed hEXT1L/EXTR1/EXTL3 (hEXT1L hereinafter) that was mapped to chromosome bands 8p12-p21 where frequent LOHs of this region was reported in breast cancer. The existence of the third breast cancer susceptibility gene was also suggested in this region by linkage analysis. We further performed LOH analysis in 8p12-p21 in 34 breast cancers and identified a 5-cM region of common allelic loss that overlapped with the locus for positive lod score in familial breast cancer. We further analyzed genomic alterations of hEXT1L in tumors in which frequent LOHs of 8p were reported. A total of 327 cancers (313 primary tumors and 14 cancer cell lines) including 22 primary breast cancers were analyzed, but none of the tumors had somatic mutations: only one thyroid cancer patient without any family history of cancer had a 9-bp insertion in the constitutional DNA. These results suggest that mutations of hEXT1L do not play a major role in the development of sporadic cancers including breast cancer, and that other tumor suppressor gene(s) exists in the 5-cM region identified in this study.
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PMID:Identification of a 5-cM region of common allelic loss on 8p12-p21 in human breast cancer and genomic analysis of the hEXT1L/EXTR1/EXTL3 gene in this locus. 1042 23

Curcumin has anti-inflammatory, antiproliferative, and antitumor effects. To understand the chemopreventive mechanism of curcumin against human malignancies, the cellular and molecular changes induced by this agent in human mammary epithelial (MCF-10A) and breast carcinoma (MCF- 7/TH) cell lines were investigated. The human multidrug- resistant breast cancer cell line was 3.5 fold more sensitive to curcumin than the mammary epithelial cell line. Even though both cell lines accumulated a similar amount of curcumin, a significantly higher percentage of apoptotic cells was induced in breast cancer cells compared to a very low percentage of apoptosis in mammary epithelial cells. Incubation of breast cancer cells with 20 and 40 microM curcumin for 24 h induced G2 block and sub-G0/G1 cell population, respectively. Curcumin treatment caused a reduction in the expression of Ki67, PCNA, and p53 mRNAs in breast cancer cells. The human mammary epithelial cell line showed a down-regulation of p21 mRNA and an up-regulation of Bax mRNA expression with curcumin treatment. The results suggest that apoptosis is involved in the curcumin-induced inhibition of tumor cell growth, and genes associated with cell proliferation and apoptosis may be playing a role in the chemopreventive action of curcumin.
Breast Cancer Res Treat 1999 Apr
PMID:Differential sensitivity of human mammary epithelial and breast carcinoma cell lines to curcumin. 1044 26

Cyclic AMP (cAMP) elevation affects growth arrest and differentiation in a wide variety of breast cell lines; however, the mechanisms associated with this process are poorly understood. Previous studies linked cAMP-mediated growth arrest in breast tumor cells to increased levels of cyclin kinase inhibitor (CKI), p21. In the present study we examined the role of cAMP-dependent protein kinase (PKA) on p21 and p27 induction in the breast cancer cell line, MDA-MB-157. The induction of the CKIs by modulators of cAMP such as cholera toxin (CT) + 1-isobutyl-3-methylxanthine (IBMX) and lovastatin fluctuates with biphasic kinetics (although the kinetics of CKI induction with CT + IBMX treatment are different from that of lovastatin) and is depicted by the periodic accumulation of lower molecular weight forms of p21 and p27 which also correlate with fluctuations in CDK2 activity. Using three different approaches we show that the cAMP-mediated induction of CKIs is independent of PKA activity. In the first approach we treated MDA-MB-157 cells with a variety of cAMP modulators such as CT + IBMX, and forskolin in the presence or absence of H-89, a potent PKA inhibitor. This analysis revealed that the cAMP activators were capable of inducing p21 even though PKA activity was completely eliminated. In the second approach PKA dominant negative stable clones of MDA-MB-157 treated with CT + IBMX or forskolin also resulted in p21 induction, in the absence of any PKA activity. Last, treatment of MDA-MB-157 cells with lovastatin, another known cAMP modulator which also causes growth arrest, resulted in the induction of p21 and p27 without any increase in PKA activity. Collectively, the above results suggest that the induction of p21 by cAMP is through a novel pathway, independent of PKA activity.
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PMID:The biphasic induction of p21 and p27 in breast cancer cells by modulators of cAMP is posttranscriptionally regulated and independent of the PKA pathway. 1050 13

Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and all-trans-retinoic acid (trans-RA) are potent regulators of growth of cancer cells. In this study, we investigated the effect of TPA and trans-RA alone or their combination on proliferation of human breast cancer ZR75-1 and T47D and lung cancer H460 and H292 cell lines. trans-RA caused various degrees of growth inhibition of these cell lines. However, TPA showed inhibition of proliferation of H460 and H292 cells and induction of ZR75-1 cell growth. Although trans-RA did not significantly regulate the growth inhibitory effect of TPA, it completely prevented its growth stimulating function. The divergent effects of TPA were associated with specific disruption of cell cycle events, an induction of G(0)/G(1) arrest in H460 and H292 cells and inhibition of G(0)/G(1) arrest with increase of S phase in ZR75-1 cells. Induction of G(0)/G(1) arrest was accompanied by induction of p21(WAF1) and ERK activity, whereas inhibition of G(0)/G(1) arrest was associated with enhanced activity of JNK and AP-1 but not ERK. trans-RA did not affect TPA-induced p21(WAF1) expression. However, it inhibited TPA-induced AP-1 activity in ZR75-1 cells and the constitutive AP-1 activity in H460 and H292 cells. Thus, trans-RA modulates TPA activity through its interaction through TPA-induced JNK/AP-1 pathway but not TPA-induced ERK/p21(WAF1) pathway.
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PMID:Differential effect of retinoic acid on growth regulation by phorbol ester in human cancer cell lines. 1051 54

BRCA1 was the first breast cancer susceptibility gene to be identified and cloned. In individuals from high-risk families, mutations in BRCA1 increase the lifetime risk of developing breast cancer eight to tenfold, compared to the general population. How the BRCA1 protein product normally functions to suppress tumor formation and how defects in the gene can ultimately lead to breast cancer have been the focus of intense scrutiny by the scientific and medical communities. BRCA1 has intrinsic transactivation activity and is able to activate the p21 promoter. In addition, BRCA1 is linked to a number of genes involved in transcriptional regulation, including CtIP, c-Myc, the RNA holoenzyme complex, and the histone deacetylase complex. Moreover, BRCA1 is essential for cellular response to DNA damage repair. Inactivation of Brca1 in mouse embryonic stem and fibroblast cells results in increased cell sensitivity to DNA-damaging agents. In human cells, BRCA1 binds to both Rad50 and Rad51 and colocalizes with these proteins at repair foci. Part of BRCA1's response to DNA damage may in fact be corroborated through transcriptional regulation. The expression of GADD45, a DNA damage-responsive gene, is increased immediately after induction of BRCA1. Recently, BRCA1 was shown to repress estradiol (E2)-responsive ER-alpha-mediated transcriptional activity, potentially linking the multiple functions of BRCA1 to specific tissue targets. These recent developments in BRCA1 function are an encouraging step toward understanding the role of BRCA1 in breast cancer formation.
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PMID:Emerging roles of BRCA1 in transcriptional regulation and DNA repair. 1052 24

The plant amino acid mimosine has been reported to block cell cycle progression in the late G1 phase. A recent study showed that mimosine might induce growth arrest by activating the expression of p21CIP1, a cyclin-dependent kinase inhibitor (CDKI), and by inhibiting the activity of cyclin E-associated kinases in human breast cancer cells. However, mimosine at higher concentrations also blocked proliferation of p21-/- cells by unknown mechanisms. In this study, we investigated the effect of mimosine on the expression of cyclins and CDKIs in human lung cancer cells. We found that mimosine specifically inhibited cyclin D1 expression in H226 cells. The expression of another G1 cyclin, cyclin E, was not regulated by mimosine in all lung cancer cell lines examined. Moreover, mimosine induced p21CIP1 expression in H226 and H358 cells, while it activated p27KIP1 expression in H322 cells. However, mimosine does not affect transcription of these genes directly because significant changes in cyclin D1 or CDKI expression were observed at 12-24 h after drug addition. Our results indicate that mimosine may block cell proliferation by multiple mechanisms and this amino acid is a useful agent for the study of cell cycle control.
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PMID:Inhibitory effect of mimosine on proliferation of human lung cancer cells is mediated by multiple mechanisms. 1053 Jul 63


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