UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence has emphasized the importance of programmed cell death or apoptosis in the maintenance of tissue homeostasis and pathogenesis of tumors. This study, analyzed in breast cancer, investigates the significance of apoptosis in relation to the expression of p53 and bcl-2 proteins, tissue proliferation defined by Ki-67 expression, hormone receptors and tumor grade. The extent of apoptosis was defined by morphological criteria and the TUNEL (Tdt-mediated dUTP biotin nick end labelling) assay. Immunocytochemistry was performed for p53, bcl-2, estrogen receptor, progesterone receptor and Ki-67 expression. Mutant p53 protein was detected using a mutant specific ELISA. Immunoreactivity of p53 significantly correlated with the presence of mutant p53 protein detected by ELISA (r = 0.654, p = 0.00001). An inverse correlation was observed between bcl-2 expression and the extent of apoptosis (r = -0.33369, p = 0.01912). The extent of apoptosis directly correlated with p53 protein accumulation (r = 0.485, p = 0.00041), Ki-67 immunoreactivity (r = 0.435, p = 0.001), histopathological grade (r = 0.492, p = 0.0003), tumor size (r = 0.326, p = 0.023) and lymph node status (r = 0.287, p = 0.047). A direct correlation was also observed between p53 expression and Ki-67 immunoreactivity (r = 0.623, p = 0.0002). There was no statistically significant association between estrogen and progesterone receptor status and apoptosis. In addition, the TNM stage of the disease correlated with immunoreactivity of p53 (r = 0.572, p = 0.00012) and Ki-67 (r = 0.3744, p = 0.00818). Bcl-2, by inhibiting apoptosis, may cause a shift in tissue kinetics towards the preservation of genetically aberrant cells, thereby facilitating tumor progression. These results imply that rapidly proliferating tumors appear to have a high "cell turnover state" in which there may be an increased chance of apoptosis amongst the proliferating cells. The ability of apoptosis to also occur in the presence of mutant p53 protein suggests the existence of at least two p53-dependent apoptotic pathways, one requiring activation of specific target genes and the other independent of it.
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PMID:Spontaneous programmed cell death in infiltrating duct carcinoma: association with p53, BCL-2, hormone receptors and tumor proliferation. 977 89

We have determined that expression of the c-myb proto-oncogene is associated with estrogen receptor (ER) status and not with tumor progression in human breast epithelial cells. Analysis of normal, immortalized, nontumorigenic, and tumorigenic mammary epithelial cells showed that only ER+ tumor cell lines expressed readily detectable levels of c-myb mRNA and a Mr 75,000 protein that was the same size as the c-myb transcripts and protein products present in hematopoietic cells. In this report we show that c-myb mRNA and protein levels are down-regulated during estrogen withdrawal. A 20-fold increase in c-myb mRNA and protein expression was observed upon addition of beta-estradiol to the culture medium. Nuclear run-on transcription analyses showed that c-myb was transcribed at the same rate in the presence and absence of estrogen, suggesting that c-myb mRNA accumulation was regulated at a posttranscriptional level. To provide additional evidence that c-myb mRNA was dependent on ER expression, we examined c-myb mRNA levels in MCF-7 cells selected for resistance to antineoplastic drugs. c-myb expression was decreased only in cell lines that showed concomitant loss of ER expression. Moreover, c-myb mRNA was expressed and modulated by estrogen in ER-, MDA-MB-231 cells stably transfected with a human ER gene. When considered together, these data indicate that c-myb mRNA levels are regulated by estrogens and further suggest that this proto-oncogene plays a role in the biology of ER+ breast tumor cells.
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PMID:Posttranscriptional regulation of the c-myb proto-oncogene in estrogen receptor-positive breast cancer cells. 981 78

This short review presents the current stage of knowledge of our laboratory on the mechanism of action of cathepsin D and estrogens on tumor progression, mostly based on studies of human breast and ovarian cancer cell lines. Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients as confirmed by a recent meta-analysis of clinical studies on node negative breast cancer patients. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of a rat tumor cells line when intravenously injected into nude mice. The mechanism of cath-D induced metastasis seems to require maturation of the pro-enzyme, mostly in large acidic compartments identified as phagosomes. Cath-D is mitogenic in different cell types, and different substrates (growth inhibitors, precursors of growth factor etc.) are proposed to mediate this activity. A mitogenic effect of the pro-enzyme on transmembrane receptor is not totally excluded. The mitogenic activity of estrogens in several estrogen receptor positive breast and ovarian cancer cell lines is well established in our and other laboratories. By contrast the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility is more controversial. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines were studied in our laboratory using a modified Boyden chamber assay. We observed, in all cases, estradiol-induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. In breast cancer cells other estrogen regulated proteins may be involved. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies, and with the better prognosis of breast cancer occurring after a prolonged treatment of menopause by estrogen as described by the collaborative group on hormonal factors in breast cancer.
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PMID:[Estrogens, cathepsin D and metastasis in cancers of the breast and ovary: invasion or proliferation?]. 984 Oct 98

Although estrogen receptor (ER)-alpha is expressed in both benign and malignant ovarian tumors, the role of ER in ovarian carcinogenesis of epithelial tumors is still unknown. In view of the recent characterization of ER-beta, a second form of ER that seems to be highly expressed in ovaries, we reexamined this issue by studying the relative expression of ER-alpha and -beta in human ovarian tumor progression. We developed a competitive PCR assay based on coamplification of the two ERs in target nucleotide sequences displaying a high homology (exons 3 and 4). Coamplification experiments with varying amounts of plasmids containing ER-alpha and -beta cDNAs showed that this assay was reliable for discriminating as little as a 2-fold difference in the initial ER-alpha:ER-beta cDNA ratio. The relative expression of ER-alpha compared with ER-beta mRNAs was studied in human ovarian cancer cell lines (n = 5) and in normal ovaries (n = 6), then in human benign and malignant tumor samples including ovarian cysts (n = 24), borderline tumors (n = 3), and cancers (n = 10). In normal ovaries, ER-beta mRNA was the predominant ER form, whereas in ovarian cancer cell lines ER-alpha mRNA was markedly increased as compared with ER-beta. In benign and borderline tumors, ER-beta mRNA was detected in 78% of tumors, whereas ER-alpha mRNA was detected in 29%. In ovarian carcinomas, both ER-alpha and -beta mRNAs were expressed in 80% of tumors. The ER-alpha:ER-beta mRNA ratio was >1 in only one cyst sample (4%). In contrast, the ER-alpha:ER-beta mRNA ratio was markedly increased in ovarian cancers because 60% showed an ER-alpha:ER-beta mRNA >1. In situ hybridization experiments showed overlapping tissular distribution of ER-beta and -alpha expression in cancers and cysts, with a main localization in the epithelium and only a low level of expression in stromal cells. In summary, we found an increase in the ER-alpha:ER-beta mRNA ratio in ovarian carcinomas as compared with normal ovaries and cysts. These data suggest that overexpression of ER-alpha relative to ER-beta mRNA may be a marker of ovarian carcinogenesis.
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PMID:Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis. 985 67

Studies from model systems suggest that matrix metalloproteinases (MMPs) are causally involved in tumor progression while tissue inhibitors of MMPs (TIMPs) prevent this progression. Here, we show that concentrations of TIMP-1 are significantly higher in breast carcinomas than in fibroadenomas. In primary breast cancers, TIMP-1 concentrations increased with increasing tumor size but showed an inverse relationship with estrogen receptor concentrations. In primary breast cancers also, TIMP-1 levels were weakly but significantly correlated with those for MMP-1, proMMP-2, active MMP-2, MMP-3 and proMMP-9. Contrary to what might be expected from published data on model systems, high concentrations of TIMP-1 predicted a poor outcome in patients with breast cancer. We conclude that in human breast cancer, endogenous TIMP-1 does not inhibit tumor progression but may enhance the process.
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PMID:High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. 998 31

The purpose of this study was to investigate apoptosis, proliferation, and the expression of apoptosis-influencing proteins bcl-2 and bax and estrogen and progesterone receptors during breast carcinoma progression. The material consisted of 53 paired breast carcinoma samples representing primary and recurrent tumors and 24 control samples. The recurrent sample was located either in the breast scar tissue or at a distant metastatic site. Apoptosis was detected both morphologically and by 3' end labeling of fragmented DNA. Cell proliferation was evaluated immunohistochemically by the MIB index. The expressions of bcl-2, bax, and estrogen and progesterone receptors were studied immunohistochemically. There was a significant increase in the extent of apoptosis and proliferation in recurrent tumors compared to the primary lesions (P = 0.015 and P = 0.038, respectively). In primary tumors with an apoptotic index of >0.50%, the survival of the patients was significantly shorter (P = 0.015). In cases with a significant increase in apoptosis or proliferation in the recurrent tumor, the survival of the patients was significantly shorter (P = 0.009 and P = 0.003, respectively). Of the variables analyzed, bcl-2 expression and a positive estrogen receptor status were significantly associated with a low extent of apoptosis (P = 0.010 and P = 0.042, respectively). Their changes were parallel to the changes in apoptosis during tumor progression, although the associations did not reach statistical significance. The results show that increased apoptosis is associated with a worse prognosis in breast carcinoma. A significant increase in apoptosis in recurrent breast carcinoma lesions predicts a worse clinical outcome.
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PMID:Apoptosis during breast carcinoma progression. 1003 80

A triple-primer PCR assay was developed, based on the coamplification of estrogen receptor (ER)-beta1, -beta2, and -beta5 cDNAs, to investigate the relative expressions of the corresponding mRNAs in breast cancer lines and in 53 independent breast tumors. The expression of ER-beta2 and ER-beta5 mRNAs was higher than that of ER-beta1 mRNA in both cancer cell lines and breast tumors. In breast tumors, increases in the ER-beta2:ER-beta1 and ER-beta5:ER-beta1 mRNA expression ratios were observed, which positively correlated with the level of tumor inflammation and tumor grade, respectively. A trend toward an increase of these ratios was also found in tumors, as compared to the normal adjacent breast tissue available for 13 cases. Our data suggest that changes in the relative expression of ER-beta1, -beta2, and -beta5 mRNAs occur during breast tumorigenesis and tumor progression.
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PMID:Expression of estrogen receptor beta1, beta2, and beta5 messenger RNAs in human breast tissue. 1009 42

The purpose of this study was to deliver tamoxifen as antiangiogenic therapy to children with recurrent progressive malignant brain tumors. Tamoxifen was administered orally in very high dosage to one child as monotherapy and to two children in combination with oral etoposide and dexamethasone. One boy was diagnosed with high-grade astrocytoma in the brain stem, one girl with anaplastic ependymoma of the fourth ventricule, and one girl with high-grade astrocytoma in the midbrain. Conventional treatment with multiple surgeries, first- and second-line chemotherapy, and external beam therapy had failed. Tumor reduction was seen in radiographic images together with clinical improvement in 2 children, and clinical and radiographic halting of tumor progression was demonstrated in the patient with anaplastic ependymoma. None of the patients developed complications from the treatment. Follow up of the patients ranged from 15 to 30 months with a mean of 17 months. These encouraging preliminary results suggest a potential for this type of therapy. More studies are needed to start clinical trials and prove that angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.
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PMID:Clinical and radiographic response in three children with recurrent malignant cerebral tumors with high-dose tamoxifen. 1032 23

The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1alpha,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer. Determination of the TaqI genotype, in a group of young women with breast cancer (n = 111; age, <37 years) and a control population (n = 130), revealed no overall association to risk for breast cancer. However, patients without TaqI site (TT genotype) showed a significantly increased risk for lymph node metastasis (relative risk, 1.8, 95% confidence interval, 1.3-2.6). Furthermore, a tendency toward an increased survival was found among estrogen receptor-positive, tamoxifen-treated patients who were homozygous for the TaqI site (P = 0.075). We conclude that polymorphism in the VDR gene may influence tumor progression and tamoxifen treatment response in early-onset breast carcinomas.
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PMID:Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. 1034 39

Protein phosphatase 2A (PP2A) acts as a growth suppressor and is negatively influenced by oncogenic signals. We determined its activity in various human breast carcinoma (HBC) cell types to understand its relationship to estrogen receptor (ER) expression as well as to the distribution of protein kinase C (PKC), an opposing enzyme. PP2A activity was measured using a preferred substrate, histone H1 phosphorylated by PKC. PP2A activity was higher in both the soluble and nuclear fractions of ER-positive cell lines (MCF-7, T47D and ZR-75-1) than in the ER-negative cell lines (MDA-MB-231, Hs578T and BT-20). PP2A multiple forms (2A0, 2A1, 2A2), separated by DEAE-cellulose chromatography and immunoblot analysis of PP2A catalytic subunit, also showed similar differences in these two HBC cell types. In all cases, PP2A distribution was inversely correlated with the PKC activity profile. Moreover, PP2A activity in MCF-7 cells maintained in estrogen-depleted medium was low. Nonetheless, it was induced by a prolonged treatment with 17beta-estradiol, this induction being blocked by the antiestrogens, tamoxifen and ICI-182,780. Studies in both MCF-7 transfectants stably overexpressing ras and MDA-MB-231 transfectants stably expressing ER, suggested that a low PP2A distribution in ER-negative HBC cell types may be related to tumor progression rather than the loss of ER. Conceivably, the presence of high PP2A along with low PKC in ER-positive HBC cell types may be related to the restricted cell growth associated with the retention of a certain degree of differentiation or hormonal control. Conversely, the presence of low PP2A along with high PKC in ER-negative cell types may be related to hormone-independent enhanced cell growth.
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PMID:Differential distribution of protein phosphatase 2A in human breast carcinoma cell lines and its relation to estrogen receptor status. 1035 43

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